WO2021091188A1 - Sustained-release pharmaceutical composition for oral administration, containing rebamipide or pharmaceutically acceptable salt thereof - Google Patents

Sustained-release pharmaceutical composition for oral administration, containing rebamipide or pharmaceutically acceptable salt thereof Download PDF

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Publication number
WO2021091188A1
WO2021091188A1 PCT/KR2020/015184 KR2020015184W WO2021091188A1 WO 2021091188 A1 WO2021091188 A1 WO 2021091188A1 KR 2020015184 W KR2020015184 W KR 2020015184W WO 2021091188 A1 WO2021091188 A1 WO 2021091188A1
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Prior art keywords
sustained
rebamipide
release
pharmaceutical composition
pharmaceutically acceptable
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PCT/KR2020/015184
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French (fr)
Korean (ko)
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박영준
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아주대학교산학협력단
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4704—2-Quinolinones, e.g. carbostyril
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants

Definitions

  • the present invention relates to a sustained-release pharmaceutical composition for oral administration comprising rebamipide or a pharmaceutically acceptable salt thereof. More specifically, chitosan is included as an anti-gelling agent and a sustained-release polymer; Or it relates to a sustained-release pharmaceutical composition for oral administration once a day or twice a day, comprising at least one anti-gelling agent and a sustained-release polymer selected from the group consisting of chitosan and amino-methacrylate copolymer.
  • Rebamipide is a substance that acts to increase the blood flow of the gastric mucosa by increasing the mucous membrane that protects the gastric wall by promoting the production of prostaglandin, and is used for gastric mucosa protection, gastric ulcer and gastritis treatment.
  • Miffy lifting lever and is sold under the trade name of a non-constant Costa TM information (Mucosta TM Tablets, Otsuka Pharmaceutical) containing 100 mg, it is administered orally three times a day. In order to increase the patient's medication convenience and compliance, it has been required to develop a rebamipide-containing pharmaceutical composition that can be administered once or twice a day.
  • Rebamipide is a very poorly soluble drug, and the solubility of rebamipide in an aqueous environment is about 0.0001% (w/v) at pH 3 and about 0.013% (w/v) at pH 7, which is more solubility in acidic conditions.
  • Rebamipide has low dissolution rate and absorption rate in the gastrointestinal tract environment after oral administration, and in order to overcome this, efforts have been attempted to increase dissolution and bioavailability by designing a formulation by micronizing drug particles or by preparing a solid dispersion ( Korean Patent No. 10-1577871).
  • Korean Patent Publication Nos. 10-2012-0075029, 10-2018-0114515, 10-2013-0121717, 10-2015-0130916, and Korean patents registered No. 10-1269829 and others have disclosed a sustained-release formulation using a gastric retention drug delivery system.
  • the gastric retention drug delivery system requires the use of a swellable polymer, and there is a large variation in gastric retention time due to differences in the ability to discharge gastric contents from person to person.
  • the present inventors conducted various studies to develop a rebamipide-containing sustained-release formulation suitable for oral administration once a day or twice a day.
  • the present inventors believe that when rebamipide is formulated in the form of tablets or the like using a conventional sustained-release polymer, the desired level of drug is not released when administered orally, while maintaining the formulated form and being discharged to the outside of the body. I discovered that there is a problem. As a result of conducting various studies to find out the cause of this problem, when rebamipide is exposed to an aqueous environment for a long time, the micronized drugs aggregate with each other or the sustained-release polymer and rebamipide aggregate to maintain the gel-like properties , It has been found that the sustained-release preparation (eg, tablet) does not disintegrate even in an aqueous solution, and the dissolution rate and absorption rate in the body are lowered.
  • the sustained-release preparation eg, tablet
  • an object of the present invention is to provide a rebamipide-containing sustained-release pharmaceutical composition suitable for oral administration once a day or twice a day containing a specific anti-gelling agent.
  • rebamipide or a pharmaceutically acceptable salt thereof comprising chitosan as an anti-gelling agent and a sustained-release polymer.
  • rebamipide or a pharmaceutically acceptable salt thereof At least one anti-gelling agent selected from the group consisting of chitosan and amino-methacrylate copolymers; And there is provided a sustained-release pharmaceutical composition for administration once a day or twice a day containing a sustained-release polymer.
  • rebamipide or a pharmaceutically acceptable salt thereof comprising a sustained-release polymer; Or rebamipide or a pharmaceutically acceptable salt thereof; Chitosan or amino-methacrylate copolymers as anti-gelling agents; And a sustained-release first layer comprising a sustained-release polymer; And rebamipide or a pharmaceutically acceptable salt thereof, and an immediate release second layer comprising a pharmaceutically acceptable additive is provided.
  • a multi-layered tablet showing a multiple release pattern of rebamipide is provided.
  • rebamipide or a pharmaceutically acceptable salt thereof comprising rebamipide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive thereof, and a capsule formulation exhibiting a multiple release pattern of rebamipide is provided.
  • rebamipide or a pharmaceutically acceptable salt thereof comprising a sustained-release polymer; Or rebamipide or a pharmaceutically acceptable salt thereof; Chitosan or amino-methacrylate copolymers as anti-gelling agents; And a sustained-release core comprising a sustained-release polymer; And an immediate release shell comprising rebamipide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive thereof.
  • a nucleated tablet showing a multiple release pattern of rebamipide.
  • the pharmaceutical composition according to the present invention contains a specific anti-gelling agent, that is, chitosan and/or an amino-methacrylate copolymer, thereby preventing aggregation between drugs or gelation due to aggregation between the sustained-release polymer and the drug. It can be formulated into a pharmaceutical composition suitable for oral administration once or twice a day.
  • Example 1 shows the dissolution test results of the sustained-release tablet of the present invention (Example 2) and the tablet not containing an anti-gelling agent (Comparative Example 1).
  • FIG 3 shows the plasma concentration profile obtained after administering the sustained-release tablet (Example 17) of the present invention and the control formulation to beagle dogs, respectively.
  • the present invention provides a sustained-release pharmaceutical composition comprising chitosan, which functions as an anti-gelling agent and a sustained-release polymer, that is, does not contain another sustained-release polymer.
  • the present invention relates to rebamipide or a pharmaceutically acceptable salt thereof; And it provides a sustained-release pharmaceutical composition for oral administration once a day or twice a day (hereinafter referred to as “first aspect” unless otherwise indicated) comprising chitosan as an anti-gelling agent and a sustained-release polymer.
  • the present invention also provides a sustained-release pharmaceutical composition comprising a chitosan and/or amino-methacrylate copolymer as an anti-gelling agent, and comprising a sustained-release polymer.
  • the present invention relates to rebamipide or a pharmaceutically acceptable salt thereof; At least one anti-gelling agent selected from the group consisting of chitosan and amino-methacrylate copolymers; And it provides a sustained-release pharmaceutical composition for administration once a day or twice a day (hereinafter, referred to as “second aspect” unless otherwise indicated) comprising a sustained-release polymer.
  • the pharmaceutical composition of the present invention contains rebamipide or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the pharmaceutically acceptable salts of rebamipide include, without limitation, salts derived from pharmacologically or physiologically acceptable amino acids and bases.
  • the amino acid include lysine, alanine, arginine, tryptophan, and the like.
  • Examples of the base include an alkali metal (eg, sodium or potassium), an alkaline earth metal (eg, magnesium), and the like.
  • Rebamipide or a pharmaceutically acceptable salt thereof may be used in a therapeutically effective amount, for example, in the range of 80 mg to 500 mg, preferably 150 mg to 300 mg per unit tablet. May contain.
  • the pharmaceutical composition of the present invention includes chitosan and/or an amino-methacrylate copolymer as an anti-gelling agent.
  • the anti-gelling agent prevents drug release from being hindered by aggregation of the drug in a low pH environment such as the stomach after oral administration, or the aggregation of the drug and the sustained-release polymer, and the drug is slowly released in the pharmaceutical composition. It plays a role in allowing it to be released. That is, the anti-gelling agent functions to continuously release the drug while preventing the formation of a release-controlling film in the form of a gel.
  • chitosan having a degree of deacetylation of 70% or more may be preferably used. If the degree of deacetylation is less than 70%, the drug may not exhibit sustained release due to insufficient release control function.
  • chitosan may not contain an additional sustained-release polymer by acting as an anti-gelling agent and a sustained-release polymer.
  • chitosan may simultaneously play a role of preventing the agglomeration of the drug and the sustained release function of the drug in the pharmaceutical composition even at a low pH.
  • chitosan is present in a range of 20 to 200 parts by weight, preferably 40 to 150 parts by weight, more preferably 70 to 120 parts by weight, based on 100 parts by weight of rebamipide. I can.
  • the content of chitosan when the content of chitosan is less than 20 parts by weight based on 100 parts by weight of rebamipide, the ability to prevent gelation may decrease, and when it exceeds 200 parts by weight, the release of the drug is controlled. You may lose your ability.
  • the pharmaceutical composition of the present invention according to the second aspect comprises chitosan and/or an amino-methacrylate copolymer as an anti-gelling agent.
  • the anti-gelling agent may be present in the range of 20 to 200 parts by weight, preferably 20 to 150 parts by weight, based on 100 parts by weight of rebamipide.
  • the content of the anti-gelling agent when the content of the anti-gelling agent is less than 20 parts by weight based on 100 parts by weight of rebamipide, the ability to prevent gelation may decrease, and when it exceeds 200 parts by weight, the drug The ability to control emissions may be impaired.
  • the weight ratio of the amino-methacrylate copolymer and chitosan is 1:1 to 10, preferably 1 : It may be in the range of 2 to 8.
  • the amino-methacrylate copolymer may be a copolymer in which butyl methacrylate, (2-dimethylaminoethyl) methacrylate, and methyl methacrylate are copolymerized in a molar ratio of 1:2:1.
  • commercially available Eudragit E PO (Evonik Industries) or the like may be used.
  • the sustained-release polymer controls the rate at which moisture penetrates into the composition in the pharmaceutical composition after oral administration or controls the rate at which rebamipide is released inside the composition. Plays a role.
  • the sustained-release polymer includes a sustained-release polymer used in the field of pharmaceuticals, for example, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl cellulose, methyl cellulose, carboxymethyl cellulose, polyethylene Oxide, polyvinyl alcohol, polyvinylpyrrolidone, xanthan gum, guar gum, carbomer, carrageenan, sodium alginate, polymethacrylate copolymers (e.g.
  • the sustained-release polymer may be preferably hydroxypropyl methylcellulose, carrageenan, or polyethylene oxide, more preferably hydroxypropyl methylcellulose.
  • the sustained-release polymer may be present in a range of 10 to 100 parts by weight, preferably 10 to 80 parts by weight, more preferably 30 to 70 parts by weight, based on 100 parts by weight of rebamipide.
  • the content of the sustained-release polymer When the content of the sustained-release polymer is less than 10 parts by weight, the ability to control the release of the drug is deteriorated, and it may be difficult to exhibit a release characteristic suitable for administration twice a day or once a day. In addition, when the content of the sustained-release polymer exceeds 100 parts by weight, the sustained-release polymer forms a gel-like release-controlling film together with the drug, so that the drug is not released and remains in the pharmaceutical composition and may be excreted out of the body. .
  • the pharmaceutical composition of the present invention may further include one or more additives selected from the group consisting of a diluent, an alkalinizing agent, a lubricant, a binder, a surfactant, a colorant, and a flavoring agent.
  • the additive may be used in an amount commonly used in the field of pharmaceuticals, and may be appropriately determined by a person skilled in the art.
  • diluent examples include lactose, glucose, microcrystalline cellulose, crystalline cellulose, calcium dihydrogen phosphate or a hydrate thereof (for example, dihydrate), mannitol, isomalt, sorbitol, pregelatinized starch, sucrose, starch (corn starch, potato Starch, etc.), lactitol, xylitol, dextrose, dextran, betacyclodextrin, a mixture of lactose and cellulose (e.g., cellactose), a mixture of silica and microcrystalline cellulose (e.g., Prosolve), maltitol And low-substituted hydroxypropyl cellulose.
  • lactose glucose, microcrystalline cellulose, crystalline cellulose, calcium dihydrogen phosphate or a hydrate thereof (for example, dihydrate), mannitol, isomalt, sorbitol, pregelatinized starch, sucrose, starch (corn starch, potato
  • alkalizing agent examples include meglumine, potassium hydrogen phosphate, sodium hydrogen phosphate, magnesium oxide, calcium carbonate, calcium hydrogen carbonate, sodium hydrogen carbonate, sodium carbonate, magnesium hydroxide, sodium hydroxide, potassium hydroxide, and the like.
  • binder examples include polyvinylpyrrolidone, gelatin, copovidone, hydroxymethyl cellulose, corn starch, sucrose, and the like.
  • surfactant examples include sodium lauryl sulfate, polysorbate (polysorbate 80, polysorbate 60, polysorbate 40, etc.), sucrose fatty acid esters, and hydrogenated castor oil (cremophor RH 40, etc.). do.
  • the lubricant is stearic acid or a salt thereof (for example, magnesium stearate, calcium stearate, etc.), aluminate metasilicate or a salt thereof, stearyl fumaric acid or a salt thereof (sodium stearyl fumarate, etc.), light anhydride silicic acid, palmitic acid, Talc, carnauba wax, hydrogenated vegetable oil, mineral oil, polyethylene glycol, and the like.
  • stearic acid or a salt thereof for example, magnesium stearate, calcium stearate, etc.
  • aluminate metasilicate or a salt thereof for example, magnesium stearate, calcium stearate, etc.
  • stearyl fumaric acid or a salt thereof sodium stearyl fumarate, etc.
  • light anhydride silicic acid palmitic acid
  • Talc carnauba wax
  • hydrogenated vegetable oil mineral oil
  • polyethylene glycol polyethylene glycol
  • the pharmaceutical composition of the present invention may have a variety of formulations, for example, tablets, compressed granules, pellets, and the like.
  • Formulations such as tablets, compressed granules, and pellets may be prepared by a granule compression method, and for example, may be prepared by a dry granulation method or a wet granulation method.
  • the pharmaceutical composition of the present invention in tablet form may be prepared by a manufacturing method comprising the following steps: (a) rebamipide or a pharmaceutically acceptable salt thereof, chitosan, and pharmaceutically acceptable Possible additives (e.g., diluents, etc.) are mixed or at least one selected from the group consisting of rebamipide or a pharmaceutically acceptable salt thereof, chitosan and amino-methacrylate copolymers, anti-gelling agents, sustained-release polymers, And mixing a pharmaceutically acceptable additive (eg, a diluent, etc.); (b) preparing dry granules from the mixture obtained in step (a) into roller compacts; And (c) mixing the dry granules obtained in step (b) with pharmaceutically acceptable additives (eg, diluents, lubricants, etc.), and tableting.
  • Possible additives e.g., diluents, etc.
  • Possible additives e.g.,
  • the pharmaceutical composition of the present invention in tablet form may be prepared by a manufacturing method comprising the following steps: (a') rebamipide or a pharmaceutically acceptable salt thereof, chitosan, and pharmaceutically Mixing acceptable additives (e.g., diluents, etc.) or rebamipide or a pharmaceutically acceptable salt thereof, at least one selected from the group consisting of chitosan and amino-methacrylate copolymers, anti-gelling agent, sustained-release polymer , And pharmaceutically acceptable additives (eg, diluents, alkalizing agents, etc.); (b') preparing wet granules using a binder solution and drying the mixture obtained in step (a'); And (c') mixing the wet granules obtained in step (b') with pharmaceutically acceptable additives (eg, alkalizing agents, lubricants, etc.) and tableting.
  • pharmaceutically acceptable additives e.g., alkalizing agents, lubricants
  • the pharmaceutical composition of the present invention in the form of compressed granules may be prepared by a manufacturing method comprising the following steps: (a'') rebamipide or a pharmaceutically acceptable salt thereof, chitosan, and Mixing pharmaceutically acceptable additives (eg, diluents, etc.) or anti-gelling agent selected from the group consisting of rebamipide or a pharmaceutically acceptable salt thereof, chitosan and amino-methacrylate copolymers, Mixing a sustained-release polymer and a pharmaceutically acceptable additive; (b'') kneading the mixture obtained in step (a'') using a binding liquid, and compression molding using an extruder; And (c'') sphericalizing the compression molded product obtained in step (b'') in a spherical granulator.
  • pharmaceutically acceptable additives eg, diluents, etc.
  • anti-gelling agent selected from the group consisting of rebami
  • the pharmaceutical composition of the present invention in the form of a pellet may be prepared by a manufacturing method comprising the following steps: (a''') comprising rebamipide or a pharmaceutically acceptable salt thereof and chitosan A mixture of rebamipide or a pharmaceutically acceptable salt thereof, an anti-gelling agent selected from the group consisting of chitosan and amino-methacrylate copolymers, and a mixture of a sustained-release polymer are combined with a binding solution (aqueous solution containing a binding agent) Or dispersing in an ethanol solution); And (b'") spraying the dispersion obtained in step (a'") onto seeds such as sugar seeds to prepare pellets.
  • the mixing may be performed according to a conventional method used in the field of pharmaceuticals.
  • the preparation of the dry granules or the preparation of tablets, compressed granules, and pellets through the preparation of wet granules may be carried out according to a conventional method used in the field of pharmaceuticals. It can be performed by compressing using a compactor or the like.
  • the tableting may also be performed according to a conventional method used in the field of pharmaceuticals. The tableting pressure can be appropriately adjusted so that a hardness of about 6-15 kp is obtained.
  • the pharmaceutical composition of the present invention may further include a conventional coating layer such as a film coating layer.
  • the film coating layer is a conventional film such as polyvinyl alcohol, hydroxypropyl cellulose, xanthan gum, lactose, hydroxypropyl methylcellulose, triacetin, polyvinylpinolidone, polyethylene glycol, propylene glycol, talc, titanium dioxide, and pigment. It may contain components for forming a coating. Film coating formation may be performed through a method such as spray coating according to a conventional method.
  • the present invention may also be formulated in the form of a formulation having a multiple release pattern, including the sustained-release pharmaceutical composition described above.
  • the formulation having the multiple release pattern is a multilayer tablet (preferably a bilayer tablet) comprising a sustained-release layer and an immediate-release layer, and It may be in the form of a tablet (ie, a nucleated tablet) having a core-shell structure including a capsule, a sustained-release core, and an immediate-release shell.
  • the sustained-release layer, sustained-release pellets or granules, and sustained-release core may be formulated according to a conventional method using the sustained-release pharmaceutical composition described above.
  • the immediate-release layer, the immediate-release pellets or granules, and the immediate-release shell may be formulated from commercially available rebamipide-containing immediate-release preparations according to a conventional method.
  • the present invention relates to rebamipide or a pharmaceutically acceptable salt thereof; And chitosan as an anti-gelling agent and a sustained-release polymer; Or rebamipide or a pharmaceutically acceptable salt thereof; Chitosan or amino-methacrylate copolymers as anti-gelling agents; And a sustained-release first layer comprising a sustained-release polymer; And a multilayer tablet showing a multiple release pattern of rebamipide comprising an immediate release second layer comprising rebamipide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive.
  • the present invention also relates to rebamipide or a pharmaceutically acceptable salt thereof; And chitosan as an anti-gelling agent and a sustained-release polymer; Or rebamipide or a pharmaceutically acceptable salt thereof; Chitosan or amino-methacrylate copolymers as anti-gelling agents; And sustained-release pellets or granules containing a sustained-release polymer; And capsules showing multiple release patterns of rebamipide or immediate-release pellets or granules containing rebamipide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive.
  • the present invention also relates to rebamipide or a pharmaceutically acceptable salt thereof; And chitosan as an anti-gelling agent and a sustained-release polymer; Or rebamipide or a pharmaceutically acceptable salt thereof; Chitosan or amino-methacrylate copolymers as anti-gelling agents; And a sustained-release core comprising a sustained-release polymer; And a nucleated tablet showing a multiple release pattern of rebamipide comprising an immediate release shell comprising rebamipide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive.
  • the immediate-release layer, the immediate-release pellet or granule, and the immediate-release shell release all rebamipide or a pharmaceutically acceptable salt thereof within 1 hour, and the sustained-release layer ,
  • the sustained-release pellets or granules, and the sustained-release core are preferably formulated to continuously release rebamipide or a pharmaceutically acceptable salt thereof for 6 hours or more.
  • a sustained-release tablet containing rebamipide was prepared according to the ingredients and contents of Table 1 below.
  • the content of each component in Table 1 represents the content per tablet (mg).
  • Rebamipide, chitosan, isomalt, sodium carbonate, amino-methacrylate copolymer, magnesium aluminate metasilicate, hydroxypropyl methylcellulose 2208, and polyvinyl pinolidone are each apologized to a 20 mesh sieve, and then rotated at high speed. Put in a granulator and mixed for about 3 minutes. To the obtained mixture, 0.06 mL of ethanol was added per tablet as a binding solution and kneaded for 5 minutes.
  • the combined product was dried in a fluid bed granulator for 2 hours, applesed through a 16 mesh sieve, and then meglumine appled through a 20 mesh sieve was added and mixed for 10 minutes.
  • Magnesium stearate was added to the finally obtained mixture, mixed for 5 minutes, and then compressed in a tablet press to have a hardness of 6 to 15 kp to prepare a sustained-release tablet.
  • a sustained-release tablet containing rebamipide was prepared according to the ingredients and contents of Table 2 below.
  • the content of each component in Table 2 represents the content per tablet (mg).
  • Rebamipide, chitosan, isomalt, sodium carbonate, magnesium aluminate metasilicate, and polyvinyl pinolidone were each apologized through a 20 mesh sieve, and then put into a high-speed rotary granulator and mixed for about 3 minutes. To the obtained mixture, 0.06 mL of ethanol was added per tablet as a binding solution and kneaded for 5 minutes.
  • the combined product was dried in a fluid bed granulator for 2 hours, applesed through a 16 mesh sieve, and then meglumine appled through a 20 mesh sieve was added and mixed for 10 minutes.
  • Magnesium stearate was added to the finally obtained mixture, mixed for 5 minutes, and then compressed in a tablet press to have a hardness of 6 to 15 kp to prepare a sustained-release tablet.
  • a two-layer tablet containing rebamipide was prepared according to the components and contents of Table 5 below.
  • the content of each component in Table 5 represents the content per tablet (mg).
  • Rebamipide, chitosan, isomalt, sodium carbonate, amino-methacrylate copolymer (Examples 17 and 18), magnesium aluminate metasilicate, sustained-release polymer (hydroxypropyl methylcellulose 2208 and/or 2910, or carrageenan) And polyvinyl pinolidone were each apologized through a 20 mesh sieve, and then put into a high-speed rotating granulator and mixed for about 3 minutes. To the obtained mixture, 0.06 mL of ethanol was added per tablet as a binding solution and kneaded for 5 minutes.
  • the combined product was dried in a fluid bed granulator for 2 hours, applesed through a 16 mesh sieve, and then meglumine (Examples 17, 19, and 20) appled through a 20 mesh sieve was added and mixed for 10 minutes. Magnesium stearate was added to the finally obtained mixture and mixed for 5 minutes to prepare a mixture A.
  • Rebamipide, microcrystalline cellulose, and low-substituted hydroxypropyl cellulose were each apologized through a 20 mesh sieve, and then put into a high-speed rotary granulator and mixed for about 3 minutes.
  • a high-speed rotary granulator a solution obtained by dissolving low-viscosity hydroxypropyl cellulose (about 1/2 of the content in Table 5) in purified water was used as a binding solution, and the obtained mixture was kneaded for 10 minutes.
  • the combined product was dried in a fluidized bed granulator for 2 hours and then apologized with a 16 mesh sieve, and then apologized with a 20 mesh sieve. ) And mixed for 10 minutes.
  • magnesium stearate was added as a lubricant and mixed for 5 minutes to prepare a mixture B.
  • the mixture A was compressed using a two-layer tablet press, and the mixture B was compressed thereon to prepare a two-layer tablet having a hardness of 6 to 15 kp.
  • Example 6 According to the components and contents of Table 6 below, in the same manner as in Example 2, a sustained-release tablet containing rebamipide (containing hydroxypropyl methylcellulose 2208 (100 cps) as a sustained-release polymer) was prepared.
  • the content of each component in Table 6 represents the content per tablet (mg).
  • the dissolution test for the sustained-release tablets prepared in Example 2 and Comparative Example 1 was performed under conditions similar to the low pH conditions in the body. Specifically, using 900 mL of a pH 4.0 dissolution test solution (a buffer solution containing acetic acid and sodium acetate), a dissolution test was performed while rotating the paddle at 37°C at 50 rpm according to the second method of dissolution test method of the Korean Pharmacopoeia. After 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, and 8 hours after the start of the test, each 5 mL was taken as a sample solution, and analyzed as follows.
  • a pH 4.0 dissolution test solution a buffer solution containing acetic acid and sodium acetate
  • Standard solution 1 was prepared by mixing 1 mL of standard stock solution and 49 mL of elution test solution.
  • Standard solution 2 Standard solution 2 was prepared by mixing 3 mL of standard stock solution and 47 mL of elution test solution.
  • Standard solution 3 was prepared by mixing 5 mL of standard stock solution and 45 mL of elution test solution.
  • Standard Solution 4 was prepared by mixing 6 mL of standard stock solution and 44 mL of elution test solution.
  • the absorbance was measured at 326 nm with an ultraviolet absorber (UV-vis absorbance photometer), and the dissolution rate (%) was calculated from the calibration curve obtained using the standard solution by the following equation.
  • Example 4 For the sustained-release tablet prepared in Example 4, a dissolution test was performed in the same manner as in Test Example 1, and the results are shown in FIG. 2. From the results of FIG. 2, the tablet obtained according to the present invention exhibited continuous elution without exhibiting a gelation phenomenon, and showed about 50% level of elution up to 12 hours, so it can be seen that continuous elution is possible up to 24 hours. .
  • Example 17 After oral administration of the tablet (bilayer tablet) prepared in Example 17 and the non-costa tablet (containing 100 mg of rebamipide) as a control preparation to a beagle dog, the concentration profile of rebamipide in the blood was measured to evaluate the in vivo kinetics. .
  • Each tablet was orally administered with 25 mL of water to beagle dogs weighing about 10 kg.
  • the tablet of Example 17 was administered at 12 hour intervals, and the control agent was administered 3 times at 6 hour intervals. At 12.5, 13, 13.5, 14, 14.5, 15, 16, 17, 18, 20, and 24 hours from 12 hours after the start of the test, take 2 mL of blood from the jugular vein of the beagle dog and immediately take 10 ul (5 units) of blood.
  • a stock solution (1 mg/mL) was prepared by dissolving 10.00 mg of rebamipide in 10 mL of acetonitrile. After diluting the stock solution with acetonitrile, 50 ⁇ L of donor plasma and 50 ⁇ L of a previously prepared working solution were added to a micro tube, and a standard concentration of 5, 10, 50, 100, 500, and 1000 ng/mL Plasma samples were prepared. To 50 ⁇ L of the prepared standard plasma sample, 50 ⁇ L of an internal standard standard solution (Rebamipide-D4, 500 ng/mL) dissolved in acetonitrile and 350 ⁇ L of acetonitrile as a precipitation solvent were added, followed by vortexing for 3 minutes to precipitate proteins.
  • an internal standard standard solution Rebamipide-D4, 500 ng/mL
  • the calibration curve was prepared by applying weighted regression (1/x) to the ratio of the peak area of the drug to the peak area of the internal standard in the plasma drug concentration range.
  • the blood concentration profile obtained by analyzing as described above is shown in FIG. 3. From the results of FIG. 3, it can be seen that the sustained-release tablet obtained according to the present invention gradually absorbs rebamipide and continuously maintains the drug concentration.

Abstract

The present invention provides a sustained-release pharmaceutical composition for oral administration once or twice a day, containing rebamipide or a pharmaceutically acceptable salt thereof, and chitosan as an anti-gelling agent and a sustained-release polymer, or containing rebamipide or a pharmaceutically acceptable salt thereof, at least one anti-gelling agent selected from the group consisting of chitosan and an amino-methacrylate copolymer, and a sustained-release polymer.

Description

레바미피드 또는 이의 약학적으로 허용가능한 염을 포함하는 경구투여용 서방성 약학 조성물Sustained-release pharmaceutical composition for oral administration containing rebamipide or a pharmaceutically acceptable salt thereof
본 발명은 레바미피드 또는 이의 약학적으로 허용가능한 염을 포함하는 경구투여용 서방성 약학 조성물에 관한 것이다. 더욱 상세하게는 겔화 방지제 및 서방성 중합체로서 키토산을 포함하거나; 또는 키토산 및 아미노-메타크릴레이트 공중합체로 이루어진 군으로부터 1종 이상 선택된 겔화 방지제 및 서방성 중합체를 포함하는, 1일 1회 혹은 1일 2회 경구투여를 위한 서방성 약학 조성물에 관한 것이다.The present invention relates to a sustained-release pharmaceutical composition for oral administration comprising rebamipide or a pharmaceutically acceptable salt thereof. More specifically, chitosan is included as an anti-gelling agent and a sustained-release polymer; Or it relates to a sustained-release pharmaceutical composition for oral administration once a day or twice a day, comprising at least one anti-gelling agent and a sustained-release polymer selected from the group consisting of chitosan and amino-methacrylate copolymer.
레바미피드(rebamipide)는 프로스타글란딘의 생성을 촉진시켜 위벽을 지키는 점막을 늘려 위점막의 혈류를 증가하는 작용을 하는 물질로서, 위점막 보호, 위궤양 및 위염의 치료를 위해 사용된다. 레바미피드는 100 mg을 함유하는 무코스타정TM 정(MucostaTM Tablets, 오츠카제약)의 상품명으로 판매되고 있으며, 1일 3회 경구투여된다. 환자의 복약 편의성 및 순응도를 높이기 위해 1일 1회 혹은 2회 투여가능한 레바미피드-함유 약학 조성물의 개발이 요구되어 왔다.Rebamipide (rebamipide) is a substance that acts to increase the blood flow of the gastric mucosa by increasing the mucous membrane that protects the gastric wall by promoting the production of prostaglandin, and is used for gastric mucosa protection, gastric ulcer and gastritis treatment. Miffy lifting lever and is sold under the trade name of a non-constant Costa TM information (Mucosta TM Tablets, Otsuka Pharmaceutical) containing 100 mg, it is administered orally three times a day. In order to increase the patient's medication convenience and compliance, it has been required to develop a rebamipide-containing pharmaceutical composition that can be administered once or twice a day.
레바미피드는 매우 난용성인 약물로서, 수성 환경에서 레바미피드 용해도는 pH 3에서 약 0.0001 %(w/v)이며, pH 7에서 약 0.013 %(w/v)로 산성조건에서 더욱 용해도가 낮다. 레바미피드는 경구 투여 후 위장관 환경에서 용해율 및 체내 흡수율이 낮아, 이를 극복하기 위해 약물 입자의 미분화하여 제형을 설계하거나 혹은 고체분산체를 제조하여 용출 및 생체이용율을 높이기 위한 노력이 시도된 바 있다(대한민국 특허 제10-1577871호). Rebamipide is a very poorly soluble drug, and the solubility of rebamipide in an aqueous environment is about 0.0001% (w/v) at pH 3 and about 0.013% (w/v) at pH 7, which is more solubility in acidic conditions. Rebamipide has low dissolution rate and absorption rate in the gastrointestinal tract environment after oral administration, and in order to overcome this, efforts have been attempted to increase dissolution and bioavailability by designing a formulation by micronizing drug particles or by preparing a solid dispersion ( Korean Patent No. 10-1577871).
레바미피드를 함유하는 서방성 제제로서, 대한민국 특허공개 제10-2012-0075029호, 제10-2018-0114515호, 제10-2013-0121717호, 제10-2015-0130916호, 및 대한민국 특허등록 제10-1269829호 등은 위체류 약물전달 시스템을 이용한 서방성 제제를 개시한 바 있다. 그러나, 위체류 약물전달 시스템은 팽윤성 고분자의 사용을 필요로 하며, 사람마다 위 내용물 배출 능력 차이에 의한 위체류 시간의 편차가 크고, 레바미피드의 특성상 위산 조건에 오래 머물러 있으면 서방성 중합체와 약물끼리 응집하여 서방출 특성을 보이지 않고 배설될 우려가 있으며, 위장에서의 팽윤으로 인한 복부 불쾌감, 음식물 영향(food effects) 등의 단점이 있다. 따라서, 1일 1회 혹은 1일 2회 경구투여에 적합한 레바미피드-함유 서방성 제제를 개발할 필요성이 당업계에 존재한다.As a sustained-release formulation containing rebamipide, Korean Patent Publication Nos. 10-2012-0075029, 10-2018-0114515, 10-2013-0121717, 10-2015-0130916, and Korean patents registered No. 10-1269829 and others have disclosed a sustained-release formulation using a gastric retention drug delivery system. However, the gastric retention drug delivery system requires the use of a swellable polymer, and there is a large variation in gastric retention time due to differences in the ability to discharge gastric contents from person to person. There is a risk of excretion without showing a sustained-release characteristic due to aggregation of each other, and there are disadvantages such as abdominal discomfort and food effects due to swelling in the stomach. Therefore, there is a need in the art to develop a rebamipide-containing sustained-release formulation suitable for oral administration once a day or twice a day.
본 발명자들은 1일 1회 혹은 1일 2회 경구투여에 적합한 레바미피드-함유 서방성 제제를 개발하기 위하여 다양한 연구를 수행하였다. The present inventors conducted various studies to develop a rebamipide-containing sustained-release formulation suitable for oral administration once a day or twice a day.
본 발명자들은 레바미피드를 통상의 서방성 중합체를 사용하여 정제 등의 형태로 제제화할 경우, 경구투여시 원하는 수준의 약물 방출이 이루어지지 않고, 제제화된 형태를 유지하며 체외로 배출되는 현상이 발생한다는 문제점이 있다는 것을 발견하였다. 이러한 문제점의 원인을 밝혀내기 위해 다양한 연구를 수행한 결과, 레바미피드가 수성 환경에 장시간 노출될 경우 미분화된 약물이 서로 응집되거나 서방성 중합체와 레바미피드가 응집되어 겔 형태의 성상을 유지함으로써, 수용액내에서도 서방성 제제(예를 들어, 정제)가 붕해되지 않고, 용출률 및 체내 흡수율이 낮아지게 된다는 것을 발견하였다. 즉, 1일 1회 혹은 1일 2회 경구투여에 적합한 레바미피드-함유 서방성 제제를 개발하기 위하여는, 약물간의 응집이나 서방성 중합체와 약물간의 응집으로 인한 겔화 현상을 방지하여야 한다는 것을 발견하였다. 본 발명자들은 이러한 겔화 현상을 방지하기 위하여, 특정 겔화 방지제를 사용하여 제제화한 결과, 1일 1회 혹은 1일 2회 경구투여에 적합한 레바미피드-함유 서방성 제제를 제조할 수 있다는 것을 발견하였다.The present inventors believe that when rebamipide is formulated in the form of tablets or the like using a conventional sustained-release polymer, the desired level of drug is not released when administered orally, while maintaining the formulated form and being discharged to the outside of the body. I discovered that there is a problem. As a result of conducting various studies to find out the cause of this problem, when rebamipide is exposed to an aqueous environment for a long time, the micronized drugs aggregate with each other or the sustained-release polymer and rebamipide aggregate to maintain the gel-like properties , It has been found that the sustained-release preparation (eg, tablet) does not disintegrate even in an aqueous solution, and the dissolution rate and absorption rate in the body are lowered. In other words, in order to develop a rebamipide-containing sustained-release formulation suitable for oral administration once a day or twice a day, it was found that aggregation between drugs or gelation caused by aggregation between the sustained-release polymer and drugs must be prevented. I did. The present inventors have found that, as a result of formulating using a specific anti-gelling agent to prevent such a gelation phenomenon, a rebamipide-containing sustained-release preparation suitable for oral administration once a day or twice a day can be prepared. .
따라서, 본 발명은 특정 겔화 방지제를 포함하는 1일 1회 혹은 1일 2회 경구투여에 적합한 레바미피드-함유 서방성 약학 조성물을 제공하는 것을 목적으로 한다.Accordingly, an object of the present invention is to provide a rebamipide-containing sustained-release pharmaceutical composition suitable for oral administration once a day or twice a day containing a specific anti-gelling agent.
본 발명의 일 태양에 따라, 레바미피드 또는 이의 약학적으로 허용가능한 염; 및 겔화 방지제 및 서방성 중합체로서 키토산을 포함하는, 1일 1회 혹은 1일 2회 경구투여를 위한 서방성 약학 조성물이 제공된다.According to one aspect of the present invention, rebamipide or a pharmaceutically acceptable salt thereof; And there is provided a sustained-release pharmaceutical composition for oral administration once a day or twice a day, comprising chitosan as an anti-gelling agent and a sustained-release polymer.
본 발명의 다른 태양에 따라, 레바미피드 또는 이의 약학적으로 허용가능한 염; 키토산 및 아미노-메타크릴레이트 공중합체로 이루어진 군으로부터 1종 이상 선택된 겔화 방지제; 및 서방성 중합체를 포함하는, 1일 1회 혹은 1일 2회 투여를 위한 서방성 약학 조성물이 제공된다.According to another aspect of the present invention, rebamipide or a pharmaceutically acceptable salt thereof; At least one anti-gelling agent selected from the group consisting of chitosan and amino-methacrylate copolymers; And there is provided a sustained-release pharmaceutical composition for administration once a day or twice a day containing a sustained-release polymer.
본 발명의 또다른 태양에 따라, 레바미피드 또는 이의 약학적으로 허용가능한 염; 및 겔화 방지제 및 서방성 중합체로서 키토산을 포함하거나; 혹은 레바미피드 또는 이의 약학적으로 허용가능한 염; 겔화 방지제로서 키토산 또는 아미노-메타크릴레이트 공중합체; 및 서방성 중합체를 포함하는 서방성 제1층; 및 레바미피드 또는 이의 약학적으로 허용가능한 염 및 약학적으로 허용가능한 첨가제를 포함하는 속방성 제2층을 포함하는 레바미피드의 다중 방출 패턴을 나타내는 다층정이 제공된다.According to another aspect of the present invention, rebamipide or a pharmaceutically acceptable salt thereof; And chitosan as an anti-gelling agent and a sustained-release polymer; Or rebamipide or a pharmaceutically acceptable salt thereof; Chitosan or amino-methacrylate copolymers as anti-gelling agents; And a sustained-release first layer comprising a sustained-release polymer; And rebamipide or a pharmaceutically acceptable salt thereof, and an immediate release second layer comprising a pharmaceutically acceptable additive is provided. A multi-layered tablet showing a multiple release pattern of rebamipide is provided.
본 발명의 또다른 태양에 따라, 레바미피드 또는 이의 약학적으로 허용가능한 염; 및 겔화 방지제 및 서방성 중합체로서 키토산을 포함하거나; 혹은 레바미피드 또는 이의 약학적으로 허용가능한 염; 겔화 방지제로서 키토산 또는 아미노-메타크릴레이트 공중합체; 및 서방성 중합체를 포함하는 서방성 펠렛 또는 과립; 및 레바미피드 또는 이의 약학적으로 허용가능한 염 및 약학적으로 허용가능한 첨가제를 포함하는 속방성 펠렛 또는 과립을 포함하는 레바미피드의 다중 방출 패턴을 나타내는 캅셀제가 제공된다.According to another aspect of the present invention, rebamipide or a pharmaceutically acceptable salt thereof; And chitosan as an anti-gelling agent and a sustained-release polymer; Or rebamipide or a pharmaceutically acceptable salt thereof; Chitosan or amino-methacrylate copolymers as anti-gelling agents; And sustained-release pellets or granules containing a sustained-release polymer; And an immediate-release pellet or granule comprising rebamipide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive thereof, and a capsule formulation exhibiting a multiple release pattern of rebamipide is provided.
또다른 태양에 따라, 레바미피드 또는 이의 약학적으로 허용가능한 염; 및 겔화 방지제 및 서방성 중합체로서 키토산을 포함하거나; 혹은 레바미피드 또는 이의 약학적으로 허용가능한 염; 겔화 방지제로서 키토산 또는 아미노-메타크릴레이트 공중합체; 및 서방성 중합체를 포함하는 서방성 코어; 및 레바미피드 또는 이의 약학적으로 허용가능한 염 및 약학적으로 허용가능한 첨가제를 포함하는 속방성 쉘을 포함하는 레바미피드의 다중 방출 패턴을 나타내는 유핵정이 제공된다.According to another aspect, rebamipide or a pharmaceutically acceptable salt thereof; And chitosan as an anti-gelling agent and a sustained-release polymer; Or rebamipide or a pharmaceutically acceptable salt thereof; Chitosan or amino-methacrylate copolymers as anti-gelling agents; And a sustained-release core comprising a sustained-release polymer; And an immediate release shell comprising rebamipide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive thereof. There is provided a nucleated tablet showing a multiple release pattern of rebamipide.
레바미피드를 통상의 서방성 중합체를 사용하여 정제 등의 형태로 제제화할 경우, 경구투여시 원하는 수준의 약물 방출이 이루어지지 않고, 제제화된 형태를 유지하며 체외로 배출되는 현상이 발생한다는 문제점이 있다는 것이 본 발명에 의해 밝혀졌으며, 이러한 원인이 수성 환경에서 약물 상호간의 응집 및/또는 서방성 중합체와 약물과의 응집으로 인한 겔화에 의한 것임이 본 발명에 의해 밝혀졌다. 본 발명에 따른 약학 조성물은 특정 겔화 방지제 즉, 키토산 및/또는 아미노-메타크릴레이트 공중합체를 포함함으로써, 약물간의 응집이나 서방성 중합체와 약물간의 응집으로 인한 겔화 현상을 방지할 수 있으며, 1일 1회 혹은 1일 2회 경구투여에 적합한 약학 조성물로 제제화될 수 있다.When rebamipide is formulated in the form of tablets using a conventional sustained-release polymer, there is a problem that the desired level of drug is not released when administered orally, and the formulated form is maintained and discharged out of the body occurs. It was found by the present invention that this is caused by the aggregation of drugs in an aqueous environment and/or gelation due to aggregation of the sustained-release polymer and the drug by the present invention. The pharmaceutical composition according to the present invention contains a specific anti-gelling agent, that is, chitosan and/or an amino-methacrylate copolymer, thereby preventing aggregation between drugs or gelation due to aggregation between the sustained-release polymer and the drug. It can be formulated into a pharmaceutical composition suitable for oral administration once or twice a day.
도 1은 본 발명의 서방화 정제(실시예 2)와 겔화 방지제를 포함하지 않은 정제(비교예 1)의 용출시험 결과를 나타낸다.1 shows the dissolution test results of the sustained-release tablet of the present invention (Example 2) and the tablet not containing an anti-gelling agent (Comparative Example 1).
도 2는 발명의 서방화 정제(실시예 4)의 용출시험 결과를 나타낸다.2 shows the results of the dissolution test of the sustained-release tablet of the present invention (Example 4).
도 3은 본 발명의 서방성 정제(실시예 17) 및 대조 제제를 비글견에 각각 투여한 후 얻어진 혈장 중 농도 프로파일을 나타낸다.3 shows the plasma concentration profile obtained after administering the sustained-release tablet (Example 17) of the present invention and the control formulation to beagle dogs, respectively.
본 발명은 겔화 방지제 및 서방성 중합체로서 기능하는 키토산을 포함하는, 즉 별도의 다른 서방성 중합체를 포함하지 않는 서방성 약학 조성물을 제공한다. 구체적으로, 본 발명은 레바미피드 또는 이의 약학적으로 허용가능한 염; 및 겔화 방지제 및 서방성 중합체로서 키토산을 포함하는, 1일 1회 혹은 1일 2회 경구투여를 위한 서방성 약학 조성물(이하, 별도로 지칭되지 않는 한 "제1 태양"이라 칭한다)을 제공한다.The present invention provides a sustained-release pharmaceutical composition comprising chitosan, which functions as an anti-gelling agent and a sustained-release polymer, that is, does not contain another sustained-release polymer. Specifically, the present invention relates to rebamipide or a pharmaceutically acceptable salt thereof; And it provides a sustained-release pharmaceutical composition for oral administration once a day or twice a day (hereinafter referred to as “first aspect” unless otherwise indicated) comprising chitosan as an anti-gelling agent and a sustained-release polymer.
본 발명은 또한 겔화 방지제로서 키토산 및/또는 아미노-메타크릴레이트 공중합체를 포함하고, 서방성 중합체를 포함하는 서방성 약학 조성물을 제공한다. 구체적으로, 본 발명은 레바미피드 또는 이의 약학적으로 허용가능한 염; 키토산 및 아미노-메타크릴레이트 공중합체로 이루어진 군으로부터 1종 이상 선택된 겔화 방지제; 및 서방성 중합체를 포함하는, 1일 1회 혹은 1일 2회 투여를 위한 서방성 약학 조성물(이하, 별도로 지칭되지 않는 한 "제2 태양"이라 칭한다)을 제공한다.The present invention also provides a sustained-release pharmaceutical composition comprising a chitosan and/or amino-methacrylate copolymer as an anti-gelling agent, and comprising a sustained-release polymer. Specifically, the present invention relates to rebamipide or a pharmaceutically acceptable salt thereof; At least one anti-gelling agent selected from the group consisting of chitosan and amino-methacrylate copolymers; And it provides a sustained-release pharmaceutical composition for administration once a day or twice a day (hereinafter, referred to as “second aspect” unless otherwise indicated) comprising a sustained-release polymer.
본 발명의 약학 조성물은 활성성분으로서 레바미피드 또는 이의 약학적으로 허용가능한 염을 포함한다. 상기 레바미피드의 약학적으로 허용가능한 염은 약리학적 또는 생리학적으로 허용되는 아미노산, 염기로부터 유도된 염을 제한 없이 포함한다. 상기 아미노산의 예로는 라이신, 알라닌, 아르기닌, 트립토판 등을 포함한다. 상기 염기의 예는 알칼리 금속(예를 들어, 나트륨 또는 칼륨), 알칼리 토금속(예를 들어, 마그네슘) 등을 포함한다. 레바미피드 또는 이의 약학적으로 허용가능한 염은 치료학적으로 유효한 양(therapeutically effective amount)으로 사용될 수 있으며, 예를 들어 단위 정제 당 80 mg ∼ 500 mg, 바람직하게는 150 mg ∼ 300 mg의 범위로 함유될 수 있다.The pharmaceutical composition of the present invention contains rebamipide or a pharmaceutically acceptable salt thereof as an active ingredient. The pharmaceutically acceptable salts of rebamipide include, without limitation, salts derived from pharmacologically or physiologically acceptable amino acids and bases. Examples of the amino acid include lysine, alanine, arginine, tryptophan, and the like. Examples of the base include an alkali metal (eg, sodium or potassium), an alkaline earth metal (eg, magnesium), and the like. Rebamipide or a pharmaceutically acceptable salt thereof may be used in a therapeutically effective amount, for example, in the range of 80 mg to 500 mg, preferably 150 mg to 300 mg per unit tablet. May contain.
본 발명의 약학조성물은 겔화 방지제로서 키토산 및/또는 아미노-메타크릴레이트 공중합체를 포함한다. 상기 겔화 방지제는 경구 투여된 후 위장과 같은 낮은 pH 환경에서 약물이 응집되어 약물 방출이 방해를 받거나 약물과 서방성 중합체가 응집되어 약물 방출이 방해되는 것을 막아 주고, 약학적 조성물 내에서 약물이 서서히 방출되도록 해주는 역할을 한다. 즉, 상기 겔화 방지제는 겔 형태의 방출 제어막 형성을 방지함과 동시에 지속적으로 약물을 방출시키는 기능을 한다.The pharmaceutical composition of the present invention includes chitosan and/or an amino-methacrylate copolymer as an anti-gelling agent. The anti-gelling agent prevents drug release from being hindered by aggregation of the drug in a low pH environment such as the stomach after oral administration, or the aggregation of the drug and the sustained-release polymer, and the drug is slowly released in the pharmaceutical composition. It plays a role in allowing it to be released. That is, the anti-gelling agent functions to continuously release the drug while preventing the formation of a release-controlling film in the form of a gel.
본 발명의 약학 조성물에 있어서, 상기 키토산은 탈아실화도(degree of deacetylation)가 70% 이상인 키토산을 바람직하게 사용할 수 있다. 탈아세틸화도가 70% 미만일 경우, 약물의 방출 제어 기능이 부족하여 지속적인 방출을 나타내지 못할 수 있다. In the pharmaceutical composition of the present invention, as the chitosan, chitosan having a degree of deacetylation of 70% or more may be preferably used. If the degree of deacetylation is less than 70%, the drug may not exhibit sustained release due to insufficient release control function.
제1 태양에 따른 본 발명의 약학 조성물에 있어서, 키토산은 겔화 방지제 및 서방성 중합체로서 작용함으로써, 추가의 서방성 중합체를 포함하지 않을 수 있다. 제1 태양에 따른 본 발명의 약학 조성물에 있어서, 키토산은 낮은 pH에서도 약학 조성물 내에서 약물의 지속방출 기능 및 약물의 응집을 막아주는 역할을 동시에 할 수 있다. 제1 태양에 따른 본 발명의 약학 조성물에 있어서, 키토산은 레바미피드 100 중량부에 대하여 20 내지 200 중량부, 바람직하게는 40 내지 150 중량부, 더욱 바람직하게는 70 내지 120 중량부의 범위로 존재할 수 있다. 제1 태양에 따른 본 발명의 약학 조성물에 있어서, 키토산의 함량이 레바미피드 100 중량부에 대하여 20 중량부 미만인 경우에는 겔화 방지 능력이 떨어질 수 있으며, 200 중량부를 초과할 경우에는 약물의 방출 제어 능력이 떨어질 수 있다.In the pharmaceutical composition of the present invention according to the first aspect, chitosan may not contain an additional sustained-release polymer by acting as an anti-gelling agent and a sustained-release polymer. In the pharmaceutical composition of the present invention according to the first aspect, chitosan may simultaneously play a role of preventing the agglomeration of the drug and the sustained release function of the drug in the pharmaceutical composition even at a low pH. In the pharmaceutical composition of the present invention according to the first aspect, chitosan is present in a range of 20 to 200 parts by weight, preferably 40 to 150 parts by weight, more preferably 70 to 120 parts by weight, based on 100 parts by weight of rebamipide. I can. In the pharmaceutical composition of the present invention according to the first aspect, when the content of chitosan is less than 20 parts by weight based on 100 parts by weight of rebamipide, the ability to prevent gelation may decrease, and when it exceeds 200 parts by weight, the release of the drug is controlled. You may lose your ability.
제2 태양에 따른 본 발명의 약학 조성물은 겔화 방지제로서 키토산 및/또는 아미노-메타크릴레이트 공중합체를 포함한다. 제2 태양에 따른 본 발명의 약학 조성물에 있어서, 상기 겔화 방지제는 레바미피드 100 중량부에 대하여 20 내지 200 중량부, 바람직하게는 20 내지 150 중량부의 범위로 존재할 수 있다. 제2 태양에 따른 본 발명의 약학 조성물에 있어서, 상기 겔화 방지제의 함량이 레바미피드 100 중량부에 대하여 20 중량부 미만인 경우에는 겔화 방지 능력이 떨어질 수 있으며, 200 중량부를 초과할 경우에는 약물의 방출 제어 능력이 저하될 수 있다. 제2 태양에 따른 본 발명의 약학 조성물이 겔화 방지제로서 아미노-메타크릴레이트 공중합체 및 키토산을 포함하는 경우, 아미노-메타크릴레이트 공중합체 및 키토산의 중량비는 1 : 1∼10, 바람직하게는 1 : 2∼8의 범위일 수 있다. 일 구현예에서, 상기 아미노-메타크릴레이트 공중합체는 부틸 메타크릴레이트, (2-디메틸아미노에틸) 메타크릴레이트, 및 메틸 메타크릴레이트가 1 : 2 : 1의 몰비로 공중합된 공중합체일 수 있다. 상기 아미노-메타크릴레이트 공중합체로는, 상업적으로 판매되는 유드라짓 E PO (Evonik Industries) 등을 사용할 수도 있다.The pharmaceutical composition of the present invention according to the second aspect comprises chitosan and/or an amino-methacrylate copolymer as an anti-gelling agent. In the pharmaceutical composition of the present invention according to the second aspect, the anti-gelling agent may be present in the range of 20 to 200 parts by weight, preferably 20 to 150 parts by weight, based on 100 parts by weight of rebamipide. In the pharmaceutical composition of the present invention according to the second aspect, when the content of the anti-gelling agent is less than 20 parts by weight based on 100 parts by weight of rebamipide, the ability to prevent gelation may decrease, and when it exceeds 200 parts by weight, the drug The ability to control emissions may be impaired. When the pharmaceutical composition of the present invention according to the second aspect contains an amino-methacrylate copolymer and chitosan as an anti-gelling agent, the weight ratio of the amino-methacrylate copolymer and chitosan is 1:1 to 10, preferably 1 : It may be in the range of 2 to 8. In one embodiment, the amino-methacrylate copolymer may be a copolymer in which butyl methacrylate, (2-dimethylaminoethyl) methacrylate, and methyl methacrylate are copolymerized in a molar ratio of 1:2:1. have. As the amino-methacrylate copolymer, commercially available Eudragit E PO (Evonik Industries) or the like may be used.
제2 태양에 따른 본 발명의 약학 조성물에 있어서, 상기 서방성 중합체는 경구 투여 후 약제학적 조성물 내에서 수분이 조성물 내부로 침투하는 속도를 조절하거나 조성물 내부에서 레바미피드가 방출되는 속도를 조절해주는 역할을 한다. 상기 서방성 중합체는 제제학 분야에서 사용되는 서방성 중합체를 포함하며, 예를 들어, 히드록시프로필 메틸셀룰로오스, 히드록시프로필 셀룰로오스, 히드록시에틸 셀룰로오스, 에틸 셀룰로오스, 메틸 셀룰로오스, 카르복메틸 셀룰로오스, 폴리에틸렌 옥사이드, 폴리비닐 알코올, 폴리비닐피롤리돈, 잔탄 검, 구아 검, 카보머, 카라기난, 알긴산 나트륨, 폴리메타크릴레이트 공중합체(예를 들어, 유드라짓 L, 유드라짓 S, 유드라짓 FS, 유드라짓 RS, 유드라짓 NS, 유드라짓 NE 등), 글리세릴 비히네이트, 글리세릴 모노스테아레이트, 세틸 알콜, 및 스테아릴 알콜로 이루어진 군으로부터 1종 이상 선택될 수 있다. 일 구현예에서, 상기 서방성 중합체는 바람직하게는 히드록시프로필 메틸셀룰로오스, 카라기난, 또는 폴리에틸렌 옥사이드일 수 있으며, 더욱 바람직하게는 히드록시프로필 메틸셀룰로오스일 수 있다. 상기 서방성 중합체는 레바미피드 100 중량부에 대하여 10 내지 100 중량부, 바람직하게는 10 내지 80 중량부, 더욱 바람직하게는 30 내지 70 중량부의 범위로 존재할 수 있다. 상기 서방성 중합체의 함량이 10 중량부 미만일 경우에는 약물의 방출 제어 능력이 떨어져 1일 2회 혹은 1일 1회 투여에 적합한 방출 특성을 나타내기 어려울 수 있다. 또한, 상기 서방화 중합체의 함량이 100 중량부를 초과할 경우에는 서방성 중합체가 약물과 함께 겔과 같은 방출 제어막을 형성하여, 약물이 방출되지 않고 약학 조성물 내에 머문 상태로 체외로 배설될 우려가 있다.In the pharmaceutical composition of the present invention according to the second aspect, the sustained-release polymer controls the rate at which moisture penetrates into the composition in the pharmaceutical composition after oral administration or controls the rate at which rebamipide is released inside the composition. Plays a role. The sustained-release polymer includes a sustained-release polymer used in the field of pharmaceuticals, for example, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl cellulose, methyl cellulose, carboxymethyl cellulose, polyethylene Oxide, polyvinyl alcohol, polyvinylpyrrolidone, xanthan gum, guar gum, carbomer, carrageenan, sodium alginate, polymethacrylate copolymers (e.g. Eudragit L, Eudragit S, Eudragit FS, Eudragit RS, Eudragit NS, Eudragit NE, etc.), glyceryl bihinate, glyceryl monostearate, cetyl alcohol, and stearyl alcohol. In one embodiment, the sustained-release polymer may be preferably hydroxypropyl methylcellulose, carrageenan, or polyethylene oxide, more preferably hydroxypropyl methylcellulose. The sustained-release polymer may be present in a range of 10 to 100 parts by weight, preferably 10 to 80 parts by weight, more preferably 30 to 70 parts by weight, based on 100 parts by weight of rebamipide. When the content of the sustained-release polymer is less than 10 parts by weight, the ability to control the release of the drug is deteriorated, and it may be difficult to exhibit a release characteristic suitable for administration twice a day or once a day. In addition, when the content of the sustained-release polymer exceeds 100 parts by weight, the sustained-release polymer forms a gel-like release-controlling film together with the drug, so that the drug is not released and remains in the pharmaceutical composition and may be excreted out of the body. .
본 발명의 약학 조성물은 희석제, 알칼리화제, 활택제, 결합제, 계면활성제, 착색제, 및 착향제로 이루어진 군으로부터 1종 이상 선택된 첨가제를 추가로 포함할 수 있다. 상기 첨가제는 제제학 분야에서 통상적으로 사용되는 양으로 사용될 수 있으며, 본 기술분야의 당업자에 의해 적절히 결정될 수 있다.The pharmaceutical composition of the present invention may further include one or more additives selected from the group consisting of a diluent, an alkalinizing agent, a lubricant, a binder, a surfactant, a colorant, and a flavoring agent. The additive may be used in an amount commonly used in the field of pharmaceuticals, and may be appropriately determined by a person skilled in the art.
상기 희석제의 예는 유당, 포도당, 미결정 셀룰로오스, 결정 셀룰로오스, 인산이수소칼슘 또는 이의 수화물(예를 들어, 2수화물), 만니톨, 이소말트, 솔비톨, 전호화 전분, 자당, 전분(옥수수 전분, 감자 전분 등), 락티톨, 자일리톨, 덱스트로스, 덱스트란, 베타시클로덱스트린, 락토오즈와 셀룰로오스의 혼합물(예를 들어, 셀락토스), 실리카와 미결정셀룰로오스의 혼합물(예를 들어, 프로솔브), 말티톨, 저치환 히드록시프로필셀룰로오스 등을 포함한다.Examples of the diluent include lactose, glucose, microcrystalline cellulose, crystalline cellulose, calcium dihydrogen phosphate or a hydrate thereof (for example, dihydrate), mannitol, isomalt, sorbitol, pregelatinized starch, sucrose, starch (corn starch, potato Starch, etc.), lactitol, xylitol, dextrose, dextran, betacyclodextrin, a mixture of lactose and cellulose (e.g., cellactose), a mixture of silica and microcrystalline cellulose (e.g., Prosolve), maltitol And low-substituted hydroxypropyl cellulose.
상기 알칼리화제의 예는 메글루민, 인산수소칼륨, 인산수소나트륨, 마그네슘 옥사이드, 탄산칼슘, 탄산수소칼슘, 탄산수소나트륨, 탄산나트륨, 수산화마그네슘, 수산화나트륨, 수산화칼륨 등을 포함한다.Examples of the alkalizing agent include meglumine, potassium hydrogen phosphate, sodium hydrogen phosphate, magnesium oxide, calcium carbonate, calcium hydrogen carbonate, sodium hydrogen carbonate, sodium carbonate, magnesium hydroxide, sodium hydroxide, potassium hydroxide, and the like.
상기 결합제의 예는 폴리비닐피롤리돈, 젤라틴, 코포비돈, 히드록시메틸 셀룰로오스, 옥수수전분, 백당 등을 포함한다.Examples of the binder include polyvinylpyrrolidone, gelatin, copovidone, hydroxymethyl cellulose, corn starch, sucrose, and the like.
상기 계면활성제의 예는 소디움 라우릴 설페이트, 폴리소르베이트(폴리소르베이트 80, 폴리소르베이트 60, 폴리소르베이트 40 등), 자당 지방산 에스테르, 및 수소화 피마자유(크레모포어 RH 40 등)을 포함한다.Examples of the surfactant include sodium lauryl sulfate, polysorbate (polysorbate 80, polysorbate 60, polysorbate 40, etc.), sucrose fatty acid esters, and hydrogenated castor oil (cremophor RH 40, etc.). do.
상기 활택제가 스테아린산 또는 이의 염(예를 들어, 스테아린산 마그네슘, 스테아린산 칼슘 등), 메타규산알루민산 또는 이의 염, 스테아릴푸마르산 또는 이의 염(스테아릴푸마르산 나트륨 등), 경질 무수규산, 팔미트산, 활석, 카르나우바 왁스, 수소화 식물성 오일, 광유, 폴리에틸렌 글리콜 등을 포함한다.The lubricant is stearic acid or a salt thereof (for example, magnesium stearate, calcium stearate, etc.), aluminate metasilicate or a salt thereof, stearyl fumaric acid or a salt thereof (sodium stearyl fumarate, etc.), light anhydride silicic acid, palmitic acid, Talc, carnauba wax, hydrogenated vegetable oil, mineral oil, polyethylene glycol, and the like.
본 발명의 약학 조성물은 다양한 제형을 가질 수 있으며, 예를 들어 정제, 압축과립, 펠렛 등의 제형을 가질 수 있다. 상기 정제, 압축과립, 펠렛 등의 제형은 과립압축법에 의해 제조될 수 있으며, 예를 들어 건식과립법 혹은 습식과립법에 의해 제조될 수 있다.The pharmaceutical composition of the present invention may have a variety of formulations, for example, tablets, compressed granules, pellets, and the like. Formulations such as tablets, compressed granules, and pellets may be prepared by a granule compression method, and for example, may be prepared by a dry granulation method or a wet granulation method.
일 구현예에서, 정제 형태의 본 발명의 약학 조성물은 하기 단계를 포함하는 제조방법에 의해 제조될 수 있다: (a) 레바미피드 또는 이의 약학적으로 허용가능한 염, 키토산, 및 약학적으로 허용가능한 첨가제(예를 들어, 희석제 등)를 혼합하거나 혹은 레바미피드 또는 이의 약학적으로 허용가능한 염, 키토산 및 아미노-메타크릴레이트 공중합체로 이루어진 군으로부터 1종 이상 선택된 겔화 방지제, 서방성 중합체, 및 약학적으로 허용가능한 첨가제(예를 들어, 희석제 등)를 혼합하는 단계; (b) 단계(a)에서 얻어진 혼합물을 롤러 컴팩트로 건식과립을 제조하는 단계; 및 (c) 단계(b)에서 얻어진 건식과립을 약학적으로 허용가능한 첨가제(예를 들어, 희석제, 활택제 등) 혼합하고, 타정하는 단계.In one embodiment, the pharmaceutical composition of the present invention in tablet form may be prepared by a manufacturing method comprising the following steps: (a) rebamipide or a pharmaceutically acceptable salt thereof, chitosan, and pharmaceutically acceptable Possible additives (e.g., diluents, etc.) are mixed or at least one selected from the group consisting of rebamipide or a pharmaceutically acceptable salt thereof, chitosan and amino-methacrylate copolymers, anti-gelling agents, sustained-release polymers, And mixing a pharmaceutically acceptable additive (eg, a diluent, etc.); (b) preparing dry granules from the mixture obtained in step (a) into roller compacts; And (c) mixing the dry granules obtained in step (b) with pharmaceutically acceptable additives (eg, diluents, lubricants, etc.), and tableting.
다른 구현예에서, 정제 형태의 본 발명의 약학 조성물은 하기 단계를 포함하는 제조방법에 의해 제조될 수 있다: (a') 레바미피드 또는 이의 약학적으로 허용가능한 염, 키토산, 및 약학적으로 허용가능한 첨가제(예를 들어, 희석제 등)를 혼합하거나 혹은 레바미피드 또는 이의 약학적으로 허용가능한 염, 키토산 및 아미노-메타크릴레이트 공중합체로 이루어진 군으로부터 1종 이상 선택된 겔화 방지제, 서방성 중합체, 및 약학적으로 허용가능한 첨가제(예를 들어, 희석제, 알칼리화제 등)를 혼합하는 단계; (b') 단계(a')에서 얻어진 혼합물을 결합액을 사용하여 습식과립을 제조하고 건조하는 단계; 및 (c') 단계(b')에서 얻어진 습식과립을 약학적으로 허용가능한 첨가제(예를 들어, 알칼리화제, 활택제 등) 혼합하고, 타정하는 단계.In another embodiment, the pharmaceutical composition of the present invention in tablet form may be prepared by a manufacturing method comprising the following steps: (a') rebamipide or a pharmaceutically acceptable salt thereof, chitosan, and pharmaceutically Mixing acceptable additives (e.g., diluents, etc.) or rebamipide or a pharmaceutically acceptable salt thereof, at least one selected from the group consisting of chitosan and amino-methacrylate copolymers, anti-gelling agent, sustained-release polymer , And pharmaceutically acceptable additives (eg, diluents, alkalizing agents, etc.); (b') preparing wet granules using a binder solution and drying the mixture obtained in step (a'); And (c') mixing the wet granules obtained in step (b') with pharmaceutically acceptable additives (eg, alkalizing agents, lubricants, etc.) and tableting.
또다른 구현예에서, 압축과립 형태의 본 발명의 약학 조성물은 하기 단계를 포함하는 제조방법에 의해 제조될 수 있다: (a'') 레바미피드 또는 이의 약학적으로 허용가능한 염, 키토산, 및 약학적으로 허용가능한 첨가제(예를 들어, 희석제 등)를 혼합하거나 혹은 레바미피드 또는 이의 약학적으로 허용가능한 염, 키토산 및 아미노-메타크릴레이트 공중합체로 이루어진 군으로부터 1종 이상 선택된 겔화 방지제, 서방성 중합체, 및 약학적으로 허용가능한 첨가제를 혼합하는 단계; (b'') 단계(a'')에서 얻어진 혼합물을 결합액을 사용하여 연합하고, 압출과립기(Extruder)를 사용하여 압축성형하는 단계; 및 (c'') 단계(b'')에서 얻어진 압축성형물을 구형과립기에서 구형화하는 단계.In another embodiment, the pharmaceutical composition of the present invention in the form of compressed granules may be prepared by a manufacturing method comprising the following steps: (a'') rebamipide or a pharmaceutically acceptable salt thereof, chitosan, and Mixing pharmaceutically acceptable additives (eg, diluents, etc.) or anti-gelling agent selected from the group consisting of rebamipide or a pharmaceutically acceptable salt thereof, chitosan and amino-methacrylate copolymers, Mixing a sustained-release polymer and a pharmaceutically acceptable additive; (b'') kneading the mixture obtained in step (a'') using a binding liquid, and compression molding using an extruder; And (c'') sphericalizing the compression molded product obtained in step (b'') in a spherical granulator.
또다른 구현예에서, 펠렛 형태의 본 발명의 약학 조성물은 하기 단계를 포함하는 제조방법에 의해 제조될 수 있다: (a''') 레바미피드 또는 이의 약학적으로 허용가능한 염 및 키토산을 포함하는 혼합물 혹은 레바미피드 또는 이의 약학적으로 허용가능한 염, 키토산 및 아미노-메타크릴레이트 공중합체로 이루어진 군으로부터 1종 이상 선택된 겔화 방지제, 및 서방성 중합체의 혼합물을 결합액(결합제를 함유하는 수용액 혹은 에탄올 용액)에 분산시키는 단계; 및 (b''') 단계(a''')에서 얻어진 분산액을 슈가 시드 등의 시드에 분사하여 펠렛을 제조하는 단계.In another embodiment, the pharmaceutical composition of the present invention in the form of a pellet may be prepared by a manufacturing method comprising the following steps: (a''') comprising rebamipide or a pharmaceutically acceptable salt thereof and chitosan A mixture of rebamipide or a pharmaceutically acceptable salt thereof, an anti-gelling agent selected from the group consisting of chitosan and amino-methacrylate copolymers, and a mixture of a sustained-release polymer are combined with a binding solution (aqueous solution containing a binding agent) Or dispersing in an ethanol solution); And (b'") spraying the dispersion obtained in step (a'") onto seeds such as sugar seeds to prepare pellets.
상기 구현예들에서 있어서, 상기 혼합은 제제학 분야에서 사용되는 통상의 방법에 따라 수행될 수 있다. 또한, 상기 건식 과립(dry granules)의 제조나 습식 과립의 제조를 통한 정제, 압축 과립, 펠렛의 제조는 제제학 분야에서 사용되는 통상의 방법에 따라 수행될 수 있으며, 예를 들어 얻어진 혼합물을 롤러 컴팩터 등을 사용하여 압축함으로써 수행될 수 있다. 상기 타정 또한 제제학 분야에서 사용되는 통상의 방법에 따라 수행될 수 있다. 타정압은 약 6∼15 kp의 경도가 얻어지도록 적절히 조절될 수 있다.In the above embodiments, the mixing may be performed according to a conventional method used in the field of pharmaceuticals. In addition, the preparation of the dry granules or the preparation of tablets, compressed granules, and pellets through the preparation of wet granules may be carried out according to a conventional method used in the field of pharmaceuticals. It can be performed by compressing using a compactor or the like. The tableting may also be performed according to a conventional method used in the field of pharmaceuticals. The tableting pressure can be appropriately adjusted so that a hardness of about 6-15 kp is obtained.
본 발명의 약학 조성물이 정제의 형태일 경우, 필름코팅층 등의 통상의 코팅층을 추가로 포함할 수 있다. 상기 필름 코팅층은 폴리비닐 알코올, 히드록시프로필 셀룰로오스, 잔탄검, 락토오스, 히드록시프로필 메틸셀룰로스, 트리아세틴, 폴리비닐피놀리돈, 폴리에틸렌 글리콜, 프로필렌 글리콜, 탈크, 티타늄 이산화물, 색소 등의 통상의 필름코팅 형성용 성분들을 포함할 수 있다. 필름코팅 형성은 통상의 방법에 따라 분무 코팅 등의 방법을 통하여 수행될 수 있다.When the pharmaceutical composition of the present invention is in the form of a tablet, it may further include a conventional coating layer such as a film coating layer. The film coating layer is a conventional film such as polyvinyl alcohol, hydroxypropyl cellulose, xanthan gum, lactose, hydroxypropyl methylcellulose, triacetin, polyvinylpinolidone, polyethylene glycol, propylene glycol, talc, titanium dioxide, and pigment. It may contain components for forming a coating. Film coating formation may be performed through a method such as spray coating according to a conventional method.
본 발명은 또한 상기한 서방성 약학 조성물을 포함하는, 다중 방출 패턴을 갖는 제제의 형태로 제제화될 수 있다. 상기 다중 방출 패턴을 갖는 제제는 서방성 층 및 속방성 층을 포함하는 다층정[바람직하게는 이층정(bilayer tablet)], 서방성 펠렛 또는 과립 및 속방성 펠렛 또는 과립을 포함하는 레바미피드의 캅셀제, 서방성 코어 및 속방성 쉘을 포함하는 코어-쉘 구조의 정제(즉, 유핵정)의 형태일 수 있다. 상기 서방성 층, 서방성 펠렛 또는 과립, 및 서방성 코어는 상기한 서방성 약학 조성물을 사용하여 통상의 방법에 따라 제제화할 수 있다. 또한, 상기 속방성 층, 속방성 펠렛 또는 과립, 및 속방성 쉘은 상업적으로 판매되는 레바미피드-함유 속방성 제제로부터 통상의 방법에 따라 제제화할 수 있다.The present invention may also be formulated in the form of a formulation having a multiple release pattern, including the sustained-release pharmaceutical composition described above. The formulation having the multiple release pattern is a multilayer tablet (preferably a bilayer tablet) comprising a sustained-release layer and an immediate-release layer, and It may be in the form of a tablet (ie, a nucleated tablet) having a core-shell structure including a capsule, a sustained-release core, and an immediate-release shell. The sustained-release layer, sustained-release pellets or granules, and sustained-release core may be formulated according to a conventional method using the sustained-release pharmaceutical composition described above. In addition, the immediate-release layer, the immediate-release pellets or granules, and the immediate-release shell may be formulated from commercially available rebamipide-containing immediate-release preparations according to a conventional method.
예를 들어, 본 발명은 레바미피드 또는 이의 약학적으로 허용가능한 염; 및 겔화 방지제 및 서방성 중합체로서 키토산을 포함하거나; 혹은 레바미피드 또는 이의 약학적으로 허용가능한 염; 겔화 방지제로서 키토산 또는 아미노-메타크릴레이트 공중합체; 및 서방성 중합체를 포함하는 서방성 제1층; 및 레바미피드 또는 이의 약학적으로 허용가능한 염 및 약학적으로 허용가능한 첨가제를 포함하는 속방성 제2층을 포함하는 레바미피드의 다중 방출 패턴을 나타내는 다층정을 포함한다.For example, the present invention relates to rebamipide or a pharmaceutically acceptable salt thereof; And chitosan as an anti-gelling agent and a sustained-release polymer; Or rebamipide or a pharmaceutically acceptable salt thereof; Chitosan or amino-methacrylate copolymers as anti-gelling agents; And a sustained-release first layer comprising a sustained-release polymer; And a multilayer tablet showing a multiple release pattern of rebamipide comprising an immediate release second layer comprising rebamipide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive.
본 발명은 또한 레바미피드 또는 이의 약학적으로 허용가능한 염; 및 겔화 방지제 및 서방성 중합체로서 키토산을 포함하거나; 혹은 레바미피드 또는 이의 약학적으로 허용가능한 염; 겔화 방지제로서 키토산 또는 아미노-메타크릴레이트 공중합체; 및 서방성 중합체를 포함하는 서방성 펠렛 또는 과립; 및 레바미피드 또는 이의 약학적으로 허용가능한 염 및 약학적으로 허용가능한 첨가제를 포함하는 속방성 펠렛 또는 과립을 포함하는 레바미피드의 다중 방출 패턴을 나타내는 캅셀제를 포함한다.The present invention also relates to rebamipide or a pharmaceutically acceptable salt thereof; And chitosan as an anti-gelling agent and a sustained-release polymer; Or rebamipide or a pharmaceutically acceptable salt thereof; Chitosan or amino-methacrylate copolymers as anti-gelling agents; And sustained-release pellets or granules containing a sustained-release polymer; And capsules showing multiple release patterns of rebamipide or immediate-release pellets or granules containing rebamipide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive.
본 발명은 또한 레바미피드 또는 이의 약학적으로 허용가능한 염; 및 겔화 방지제 및 서방성 중합체로서 키토산을 포함하거나; 혹은 레바미피드 또는 이의 약학적으로 허용가능한 염; 겔화 방지제로서 키토산 또는 아미노-메타크릴레이트 공중합체; 및 서방성 중합체를 포함하는 서방성 코어; 및 레바미피드 또는 이의 약학적으로 허용가능한 염 및 약학적으로 허용가능한 첨가제를 포함하는 속방성 쉘을 포함하는 레바미피드의 다중 방출 패턴을 나타내는 유핵정을 포함한다.The present invention also relates to rebamipide or a pharmaceutically acceptable salt thereof; And chitosan as an anti-gelling agent and a sustained-release polymer; Or rebamipide or a pharmaceutically acceptable salt thereof; Chitosan or amino-methacrylate copolymers as anti-gelling agents; And a sustained-release core comprising a sustained-release polymer; And a nucleated tablet showing a multiple release pattern of rebamipide comprising an immediate release shell comprising rebamipide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive.
본 발명에 따른 다중 방출 패턴을 갖는 제제에 있어서, 상기 속방성층, 속방성 펠렛 또는 과립, 및 속방성 쉘은 1시간 이내에 레바미피드 또는 이의 약학적으로 허용가능한 염을 모두 방출시키고, 상기 서방성층, 서방성 펠렛 또는 과립, 및 서방성 코어는 레바미피드 또는 이의 약학적으로 허용가능한 염을 6시간 이상 지속적으로 방출시키도록 제제화하는 것이 바람직하다.In the formulation having a multiple release pattern according to the present invention, the immediate-release layer, the immediate-release pellet or granule, and the immediate-release shell release all rebamipide or a pharmaceutically acceptable salt thereof within 1 hour, and the sustained-release layer , The sustained-release pellets or granules, and the sustained-release core are preferably formulated to continuously release rebamipide or a pharmaceutically acceptable salt thereof for 6 hours or more.
이하, 본 발명을 실시예 및 시험예를 통하여 더욱 상세히 설명한다. 그러나, 하기 실시예 및 시험예는 본 발명을 예시하기 위한 것으로, 본 발명이 이들에 의해 제한되는 것은 아니다. Hereinafter, the present invention will be described in more detail through Examples and Test Examples. However, the following Examples and Test Examples are for illustrating the present invention, and the present invention is not limited thereto.
실시예 1. Example 1.
하기 표 1의 성분 및 함량에 따라 레바미피드를 함유하는 서방성 정제를 제조하였다. 표 1의 각 성분의 함량은 정제당 함량(mg)을 나타낸다. 레바미피드, 키토산, 이소말트, 탄산나트륨, 아미노-메타크릴레이트 공중합체, 메타규산알루민산마그네슘, 히드록시프로필 메틸셀룰로오스 2208, 및 폴리비닐피놀리돈을 각각 20메쉬 체망에 사과한 후, 고속회전과립기에 넣고 약 3분간 혼합하였다. 얻어진 혼합물에 결합액으로 에탄올을 1정당 0.06 mL 넣고 5분간 연합하였다. 연합물을 유동층 과립기에서 2시간 건조하고 16메쉬체로 사과한 다음, 20메쉬체망으로 사과한 메글루민을 넣고 10분간 혼합하였다. 최종적으로 얻어진 혼합물에 스테아린산 마그네슘을 넣고 5분간 혼합한 다음, 타정기에서 경도가 6∼15kp가 되도록 압축하여 서방성 정제를 제조하였다.A sustained-release tablet containing rebamipide was prepared according to the ingredients and contents of Table 1 below. The content of each component in Table 1 represents the content per tablet (mg). Rebamipide, chitosan, isomalt, sodium carbonate, amino-methacrylate copolymer, magnesium aluminate metasilicate, hydroxypropyl methylcellulose 2208, and polyvinyl pinolidone are each apologized to a 20 mesh sieve, and then rotated at high speed. Put in a granulator and mixed for about 3 minutes. To the obtained mixture, 0.06 mL of ethanol was added per tablet as a binding solution and kneaded for 5 minutes. The combined product was dried in a fluid bed granulator for 2 hours, applesed through a 16 mesh sieve, and then meglumine appled through a 20 mesh sieve was added and mixed for 10 minutes. Magnesium stearate was added to the finally obtained mixture, mixed for 5 minutes, and then compressed in a tablet press to have a hardness of 6 to 15 kp to prepare a sustained-release tablet.
성 분ingredient mg/정mg/tablet
레바미피드Rebamifeed 150150
키토산Chitosan 116.7116.7
아미노-메타크릴레이트 공중합체(Eudragit E PO)Amino-methacrylate copolymer (Eudragit E PO) 33.333.3
히드록시프로필 메틸셀룰로오스 2208 (100 cps)Hydroxypropyl methylcellulose 2208 (100 cps) 33.333.3
메타규산알루민산마그네슘(Neusilin US2)Magnesium aluminate metasilicate (Neusilin US2) 6.76.7
탄산나트륨 Sodium carbonate 5050
이소말트Isomalt 75 75
폴리비닐피놀리돈(PVP K90)Polyvinyl pinolidone (PVP K90) 55
메글루민Meglumine 2525
스테아린산 마그네슘 Magnesium stearate 55
1정 정제 중량(mg)Tablet weight per tablet (mg) 500500
실시예 2. Example 2.
하기 표 2의 성분 및 함량에 따라 레바미피드를 함유하는 서방성 정제를 제조하였다. 표 2의 각 성분의 함량은 정제당 함량(mg)을 나타낸다. 레바미피드, 키토산, 이소말트, 탄산나트륨, 메타규산알루민산마그네슘, 및 폴리비닐피놀리돈을 각각 20메쉬 체망에 사과한 후, 고속회전과립기에 넣고 약 3분간 혼합하였다. 얻어진 혼합물에 결합액으로 에탄올을 1정당 0.06 mL 넣고 5분간 연합하였다. 연합물을 유동층 과립기에서 2시간 건조하고 16메쉬체로 사과한 다음, 20메쉬체망으로 사과한 메글루민을 넣고 10분간 혼합하였다. 최종적으로 얻어진 혼합물에 스테아린산 마그네슘을 넣고 5분간 혼합한 다음, 타정기에서 경도가 6∼15kp가 되도록 압축하여 서방성 정제를 제조하였다.A sustained-release tablet containing rebamipide was prepared according to the ingredients and contents of Table 2 below. The content of each component in Table 2 represents the content per tablet (mg). Rebamipide, chitosan, isomalt, sodium carbonate, magnesium aluminate metasilicate, and polyvinyl pinolidone were each apologized through a 20 mesh sieve, and then put into a high-speed rotary granulator and mixed for about 3 minutes. To the obtained mixture, 0.06 mL of ethanol was added per tablet as a binding solution and kneaded for 5 minutes. The combined product was dried in a fluid bed granulator for 2 hours, applesed through a 16 mesh sieve, and then meglumine appled through a 20 mesh sieve was added and mixed for 10 minutes. Magnesium stearate was added to the finally obtained mixture, mixed for 5 minutes, and then compressed in a tablet press to have a hardness of 6 to 15 kp to prepare a sustained-release tablet.
성 분ingredient mg/정mg/tablet
레바미피드Rebamifeed 150150
키토산Chitosan 183.3183.3
메타규산알루민산마그네슘Magnesium aluminate metasilicate 6.76.7
탄산나트륨 Sodium carbonate 5050
이소말트Isomalt 75 75
폴리비닐피놀리돈(PVP K90)Polyvinyl pinolidone (PVP K90) 55
메글루민Meglumine 2525
스테아린산 마그네슘 Magnesium stearate 55
1정 정제 중량(mg)Tablet weight per tablet (mg) 500500
실시예 3∼16. Examples 3 to 16.
하기 표 3 및 4의 성분 및 함량에 따라, 실시예 1과 동일한 방법으로, 레바미피드를 함유하는 서방성 정제를 제조하였다. 표 3 및 4의 각 성분의 함량은 정제당 함량(mg)을 나타낸다. According to the components and contents of Tables 3 and 4 below, in the same manner as in Example 1, a sustained-release tablet containing rebamipide was prepared. The content of each component in Tables 3 and 4 represents the content (mg) per tablet.
성 분ingredient 실시예 (mg/정)Example (mg/tablet)
33 44 55 66 77 88 99
레바미피드Rebamifeed 9090 200200 150150 150150 150150 150150 9090
키토산Chitosan 5555 82.282.2 165165 165165 150150 116.7116.7 6060
아미노-메타크릴레이트 공중합체(Eudragit E PO)Amino-methacrylate copolymer (Eudragit E PO) -- 82.282.2 -- -- -- 33.333.3 1010
히드록시프로필 메틸셀룰로오스 2208 (100 cps)Hydroxypropyl methylcellulose 2208 (100 cps) 5555 82.282.2 -- -- -- -- 4040
히드록시프로필 메틸셀룰로오스 2208 (15000cps)Hydroxypropyl Methylcellulose 2208 (15000cps) -- -- -- -- -- 33.333.3 --
히드록시프로필 메틸셀룰로오스 2910 (4000cps)Hydroxypropyl methylcellulose 2910 (4000cps) -- -- -- -- 3030 -- --
카라기난Carrageenan -- -- -- 1515 -- -- --
폴리에틸렌 옥사이드 303Polyethylene oxide 303 -- -- 1515 -- -- -- --
메타규산알루민산마그네슘 Magnesium aluminate metasilicate 44 8.98.9 -- -- -- 44 44
탄산나트륨 Sodium carbonate 3030 64.464.4 5050 5050 5050 7575 4545
이소말트Isomalt 4545 100100 -- -- -- 7575 4545
만니톨Mannitol -- -- 7575 7575 7575 -- --
폴리비닐피놀리돈 (PVP K90)Polyvinylpinolidone (PVP K90) 33 6.76.7 55 55 55 55 33
메글루민Meglumine 1515 33.333.3 2525 2525 2525 -- --
스테아린산 마그네슘 Magnesium stearate 33 6.76.7 55 55 55 55 33
1정 정제 중량(mg)Tablet weight per tablet (mg) 300300 666.7666.7 500500 500500 500500 500500 300300
성 분ingredient 실시예 (mg/정)Example (mg/tablet)
1010 1111 1212 1313 1414 1515 1616
레바미피드 Rebamifeed 100100 100100 100100 100100 100100 100100 100100
키토산 Chitosan 1010 4040 9696 -- 7070 150150 5050
아미노-메타크릴레이트 공중합체(Eudragit E PO)Amino-methacrylate copolymer (Eudragit E PO) 1010 4040 -- 4040 2020 -- --
히드록시프로필 메틸셀룰로오스 2208 (100 cps)Hydroxypropyl methylcellulose 2208 (100 cps) 8080 4040 -- 8080 4040 --
히드록시프로필 메틸셀룰로오스 2910 (4000cps)Hydroxypropyl methylcellulose 2910 (4000cps) -- -- 2424 -- -- 4040 --
폴리에틸렌 옥사이드 301Polyethylene oxide 301 -- -- -- -- -- 4040
탄산나트륨 Sodium carbonate 8080 100100 100100 8080 -- 5050 4040
이소말트 Isomalt 6060 44.444.4 44.444.4 4040 4040 5050
만니톨Mannitol -- -- -- -- -- 5555 --
폴리비닐피놀리돈(PVP K90)Polyvinyl pinolidone (PVP K90) 55 -- -- -- -- 33
메글루민Meglumine -- -- -- -- 8080 1010
스테아린산 마그네슘 Magnesium stearate 55 5.65.6 5.65.6 55 55 55 33
1정 정제 중량(mg)Tablet weight per tablet (mg) 350350 350350 350350 350350 330330 400400 300300
실시예 17∼20. Examples 17-20.
하기 표 5의 성분 및 함량에 따라 레바미피드를 함유하는 이층정을 제조하였다. 표 5의 각 성분의 함량은 정제당 함량(mg)을 나타낸다. A two-layer tablet containing rebamipide was prepared according to the components and contents of Table 5 below. The content of each component in Table 5 represents the content per tablet (mg).
레바미피드, 키토산, 이소말트, 탄산나트륨, 아미노-메타크릴레이트 공중합체(실시예 17 및 18), 메타규산알루민산마그네슘, 서방성 중합체(히드록시프로필 메틸셀룰로오스 2208 및/또는 2910, 또는 카라기난) 및 폴리비닐피놀리돈을 각각 20메쉬 체망에 사과한 후, 고속회전과립기에 넣고 약 3분간 혼합하였다. 얻어진 혼합물에 결합액으로 에탄올을 1정당 0.06 mL 넣고 5분간 연합하였다. 연합물을 유동층 과립기에서 2시간 건조하고 16메쉬체로 사과한 다음, 20메쉬체망으로 사과한 메글루민(실시예 17, 19, 및 20)을 넣고 10분간 혼합하였다. 최종적으로 얻어진 혼합물에 스테아린산 마그네슘을 넣고 5분간 혼합하여 혼합물 A를 제조하였다. Rebamipide, chitosan, isomalt, sodium carbonate, amino-methacrylate copolymer (Examples 17 and 18), magnesium aluminate metasilicate, sustained-release polymer (hydroxypropyl methylcellulose 2208 and/or 2910, or carrageenan) And polyvinyl pinolidone were each apologized through a 20 mesh sieve, and then put into a high-speed rotating granulator and mixed for about 3 minutes. To the obtained mixture, 0.06 mL of ethanol was added per tablet as a binding solution and kneaded for 5 minutes. The combined product was dried in a fluid bed granulator for 2 hours, applesed through a 16 mesh sieve, and then meglumine (Examples 17, 19, and 20) appled through a 20 mesh sieve was added and mixed for 10 minutes. Magnesium stearate was added to the finally obtained mixture and mixed for 5 minutes to prepare a mixture A.
레바미피드, 미결정셀룰로오스, 및 저치환도 히드록시프로필셀룰로오스(표 5의 함량 중 약 1/2)를 각각 20메쉬 체망에 사과한 후, 고속회전과립기에 넣고 약 3분간 혼합하였다. 고속회전과립기에서, 정제수에 저점도 히드록시프로필셀룰로오스(표 5의 함량 중 약 1/2)를 용해시켜 얻어진 용액을 결합액으로 사용하여, 얻어진 혼합물을 10분간 연합하였다. 연합물을 유동층 과립기에서 2시간 건조하고 16메쉬체로 사과한 다음, 20메쉬체로 사과한 저치환도 히드록시프로필셀룰로오스(표 5의 나머지 량), 저점도 히드록시메틸셀룰로오스(표 5의 나머지 량)를 넣고 10분간 혼합하였다. 최종적으로 얻어진 혼합물에 활택제로 스테아린산 마그네슘을 넣고 5분간 혼합하여 혼합물 B를 제조하였다. Rebamipide, microcrystalline cellulose, and low-substituted hydroxypropyl cellulose (about 1/2 of the contents in Table 5) were each apologized through a 20 mesh sieve, and then put into a high-speed rotary granulator and mixed for about 3 minutes. In a high-speed rotary granulator, a solution obtained by dissolving low-viscosity hydroxypropyl cellulose (about 1/2 of the content in Table 5) in purified water was used as a binding solution, and the obtained mixture was kneaded for 10 minutes. The combined product was dried in a fluidized bed granulator for 2 hours and then apologized with a 16 mesh sieve, and then apologized with a 20 mesh sieve. ) And mixed for 10 minutes. To the finally obtained mixture, magnesium stearate was added as a lubricant and mixed for 5 minutes to prepare a mixture B.
이층 타정기를 사용하여 상기 혼합물 A를 압축하고, 그 위에 혼합물 B를 압축하여 경도가 6∼15kp가 되도록 이층정을 제조하였다.The mixture A was compressed using a two-layer tablet press, and the mixture B was compressed thereon to prepare a two-layer tablet having a hardness of 6 to 15 kp.
성 분ingredient 실시예(mg/정)Example (mg/tablet)
1717 1818 1919 2020
속방층 Immediate release 레바미피드Rebamifeed 6060 6060 5050 52.552.5
미결정셀룰로오스 PH101Microcrystalline Cellulose PH101 1818 1818 1818 25.525.5
저치환도 히드록시프로필셀룰로오스Low Substitution Hydroxypropyl Cellulose 2727 2727 2727 2727
저점도 히드록시프로필셀룰로오스Low viscosity hydroxypropyl cellulose 44 44 44 44
스테아르산마그네슘Magnesium stearate 1One 1One 1One
서방층Western 레바미피드Rebamifeed 9090 9090 100100 97.597.5
키토산 Chitosan 7070 6060 4040 92.892.8
아미노-메타크릴레이트 공중합체
(Eudragit E PO)Amino-methacrylate copolymer
(Eudragit E PO) 		2020 1010 -- --
히드록시프로필 메틸셀룰로오스 2208Hydroxypropyl methylcellulose 2208 2020 4040 1010 18.618.6
히드록시프로필 메틸셀룰로오스 2910Hydroxypropyl methylcellulose 2910 -- -- -- 18.618.6
카라기난Carrageenan -- -- 4040 --
메타규산알루민산마그네슘 Magnesium aluminate metasilicate 44 44 44 4.64.6
탄산나트륨 Sodium carbonate 3030 4545 3030 35.235.2
이소말트Isomalt 4545 4545 5050 79.879.8
폴리비닐피놀리돈 K90 Polyvinyl pinolidone K90 33 33 33 7.47.4
메글루민Meglumine 1515 -- 1010 18.618.6
스테아린산 마그네슘 Magnesium stearate 33 33 33 5.75.7
1정 정제 중량(mg)Tablet weight per tablet (mg) 410410 410410 400400 488.8488.8
비교예 1Comparative Example 1
하기 표 6의 성분 및 함량에 따라, 실시예 2와 동일한 방법으로, 레바미피드를 함유하는 서방성 정제(서방성 중합체로서 히드록시프로필 메틸셀룰로오스 2208 (100 cps) 함유)를 제조하였다. 표 6의 각 성분의 함량은 정제당 함량(mg)을 나타낸다. According to the components and contents of Table 6 below, in the same manner as in Example 2, a sustained-release tablet containing rebamipide (containing hydroxypropyl methylcellulose 2208 (100 cps) as a sustained-release polymer) was prepared. The content of each component in Table 6 represents the content per tablet (mg).
성 분ingredient mg/정mg/tablet
레바미피드Rebamifeed 150150
히드록시프로필 메틸셀룰로오스 2208 (100 cps)Hydroxypropyl methylcellulose 2208 (100 cps) 183.3183.3
메타규산알루민산마그네슘Magnesium aluminate metasilicate 6.76.7
탄산나트륨 Sodium carbonate 5050
이소말트Isomalt 75 75
폴리비닐피놀리돈(PVP K90)Polyvinyl pinolidone (PVP K90) 55
메글루민Meglumine 2525
스테아린산 마그네슘 Magnesium stearate 55
1정 정제 중량(mg)Tablet weight per tablet (mg) 500500
시험예 1Test Example 1
실시예 2 및 비교예 1에서 제조한 서방성 정제에 대한 용출시험을, 체내의 낮은 pH 조건과 유사한 조건에서 수행하였다. 구체적으로, pH 4.0의 용출시험액(아세트산 및 아세트산 나트륨을 함유하는 완충액) 900 mL을 사용하여 대한민국 약전 용출시험법 제2법에 따라 37℃에서 50 rpm으로 패들을 회전시키면서 용출시험을 수행하였다. 시험 시작 후 30분, 1시간, 2시간, 3시간, 4시간, 6시간, 8시간 후에 각각 5 mL를 취하여 검액으로 하여, 다음과 같이 분석하였다.The dissolution test for the sustained-release tablets prepared in Example 2 and Comparative Example 1 was performed under conditions similar to the low pH conditions in the body. Specifically, using 900 mL of a pH 4.0 dissolution test solution (a buffer solution containing acetic acid and sodium acetate), a dissolution test was performed while rotating the paddle at 37°C at 50 rpm according to the second method of dissolution test method of the Korean Pharmacopoeia. After 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, and 8 hours after the start of the test, each 5 mL was taken as a sample solution, and analyzed as follows.
<표준원액의 제조><Preparation of standard stock solution>
레바미피드 표준품 166.7 mg을 N,N-디메틸포름아미드 100 mL에 용해시켜 표준원액(농도: 1.667 mg/mL)을 제조하였다.166.7 mg of rebamipide standard was dissolved in 100 mL of N,N-dimethylformamide to prepare a standard stock solution (concentration: 1.667 mg/mL).
<표준액의 제조><Preparation of standard solution>
표준액 1: 표준원액 1 mL 및 용출시험액 49 mL을 혼합하여 표준액 1을 제조하였다.Standard solution 1: Standard solution 1 was prepared by mixing 1 mL of standard stock solution and 49 mL of elution test solution.
표준액 2: 표준원액 3 mL 및 용출시험액 47 mL을 혼합하여 표준액 2를 제조하였다.Standard solution 2: Standard solution 2 was prepared by mixing 3 mL of standard stock solution and 47 mL of elution test solution.
표준액 3: 표준원액 5 mL 및 용출시험액 45 mL을 혼합하여 표준액 3을 제조하였다.Standard solution 3: Standard solution 3 was prepared by mixing 5 mL of standard stock solution and 45 mL of elution test solution.
표준액 4 : 표준원액 6 mL 및 용출시험액 44 mL을 혼합하여 표준액 4를 제조하였다.Standard Solution 4: Standard Solution 4 was prepared by mixing 6 mL of standard stock solution and 44 mL of elution test solution.
<분석방법> <Analysis method>
표준액과 검액에 대하여 자외선흡광광도계(UV-vis 흡광광도계)로 326 nm에서 흡광도를 측정하였으며, 표준액을 사용하여 얻어진 검량선으로부터 용출률(%)을 하기 식에 의해 계산하였다.For the standard solution and the sample solution, the absorbance was measured at 326 nm with an ultraviolet absorber (UV-vis absorbance photometer), and the dissolution rate (%) was calculated from the calibration curve obtained using the standard solution by the following equation.
Figure PCTKR2020015184-appb-I000001
Figure PCTKR2020015184-appb-I000001
AT: 검액의 흡광도A T : absorbance of the sample solution
I: 검량선의 절편I: Intercept of the calibration curve
S: 검량선의 기울기S: slope of calibration curve
D: 레바미피드 이론 함유량(mg)D: Theoretical content of rebamipide (mg)
상기와 같이 용출시험을 수행한 결과는 도 1과 같다. 도 1의 결과로부터 알 수 있는 바와 같이, 겔화 방지제를 함유하지 않은 비교예 1의 정제는 레바미피드의 용출이 20% 이내에서 머무름에 반하여, 본 발명에 따라 얻어진 정제는 레바미피드가 지속적으로 방출되고 있다.The results of performing the dissolution test as described above are shown in FIG. 1. As can be seen from the results of FIG. 1, the tablet of Comparative Example 1 containing no anti-gelling agent retained the elution of rebamipide within 20%, whereas the tablet obtained according to the present invention contained rebamipide continuously. It is being released.
시험예 2.Test Example 2.
실시예 4에서 제조한 서방성 정제에 대하여, 시험예 1과 동일한 방법으로 용출시험을 수행하였으며, 그 결과는 도2와 같다. 도 2의 결과로부터, 본 발명에 따라 얻어진 정제는 겔화 현상을 나타내지 않으면서 지속적인 용출을 나타내었으며, 12시간까지 약 50% 수준의 용출을 나타내었으므로, 24시간까지 지속적인 용출이 가능함을 알 수 있다.For the sustained-release tablet prepared in Example 4, a dissolution test was performed in the same manner as in Test Example 1, and the results are shown in FIG. 2. From the results of FIG. 2, the tablet obtained according to the present invention exhibited continuous elution without exhibiting a gelation phenomenon, and showed about 50% level of elution up to 12 hours, so it can be seen that continuous elution is possible up to 24 hours. .
시험예 3.Test Example 3.
실시예 17에서 제조한 정제(이층정) 및 대조제제로서 무코스타정(레바미피드 100 mg 함유)을 비글견에 경구투여한 후, 혈중 레바미피드의 농도 프로파일을 측정하여 체내 동태를 평가하였다. 약 10 kg 전후의 비글견에 각각의 정제를 25mL의 물과 함께 경구투여하였다. 실시예 17의 정제는 12시간 간격으로 투여하고, 대조제제는 6시간 간격으로 3회 투여하였다. 시험 시작 12시간 경과시점으로부터 12.5, 13, 13.5, 14, 14.5, 15, 16, 17, 18, 20, 24 시간 시점에서 비글견의 경정맥에서 2 mL의 혈액을 취하여 즉시 10 ul(5 unit)의 헤파린 처리된 에펜도르프 튜브에 담고, 각 시간에 얻어진 혈액 샘플은 4,000 rpm으로 10분 동안 4℃에서 원심분리하였다. 분리된 상층액을 1.5 ml 에펜도르프 튜브에 400 ul 를 1 set로 분주하고, 잔여 혈장은 다른 1 set에 담아서 채혈 포인트당 총 2 set를 만들어, -80 ℃에서 보관한 후 LC/MS/MS를 사용하여 하기 조건하에서 혈중 레바미피드의 양을 분석하였다.After oral administration of the tablet (bilayer tablet) prepared in Example 17 and the non-costa tablet (containing 100 mg of rebamipide) as a control preparation to a beagle dog, the concentration profile of rebamipide in the blood was measured to evaluate the in vivo kinetics. . Each tablet was orally administered with 25 mL of water to beagle dogs weighing about 10 kg. The tablet of Example 17 was administered at 12 hour intervals, and the control agent was administered 3 times at 6 hour intervals. At 12.5, 13, 13.5, 14, 14.5, 15, 16, 17, 18, 20, and 24 hours from 12 hours after the start of the test, take 2 mL of blood from the jugular vein of the beagle dog and immediately take 10 ul (5 units) of blood. It was placed in a heparin-treated Eppendorf tube, and the blood sample obtained at each time was centrifuged at 4° C. for 10 minutes at 4,000 rpm. Dispense the separated supernatant into 1 set of 400 ul into a 1.5 ml Eppendorf tube, and put the remaining plasma in another 1 set to make a total of 2 sets per blood collection point. It was used to analyze the amount of rebamipide in blood under the following conditions.
<LC/MS/MS 분석조건><LC/MS/MS analysis conditions>
(1) HPLC 조건(1) HPLC conditions
Figure PCTKR2020015184-appb-I000002
Figure PCTKR2020015184-appb-I000002
(2) LC/MS/MS 분석조건(2) LC/MS/MS analysis conditions
Figure PCTKR2020015184-appb-I000003
Figure PCTKR2020015184-appb-I000003
<3> 검량선 작성<3> Preparation of calibration curve
레바미피드 10.00 mg을 아세토니트릴 10 mL에 용해하여 스톡 용액(1 mg/mL)을 제조하였다. 스톡 용액을 아세토니트릴로 희석한 후 마이크로 튜브(Micro tube)에 공혈장 50 μL 와 미리 제조한 용액(working solution) 50 μL 를 가하여 5, 10, 50, 100, 500, 1000 ng/mL 농도의 표준혈장시료를 제조하였다. 제조된 표준혈장시료 50 μL에 아세토니트릴에 용해한 내부표준물질 표준용액(Rebamipide-D4, 500 ng/mL) 50 μL 와 침전용매로서 아세토니트릴 350 μL을 가한 후 3분간 볼텍싱하여 단백질을 침전시켰다. 이 용액을 20000 g 에서 15분간 원심 분리한 후 상층액 100 μL 를 증류수 100 μL에 가하여 3분간 볼텍싱한 후, 5 μL를 LC-MS/MS에 주입하였다. 검량선은 혈장 약물농도 범위에서 내부표준물질의 피크 면적에 대한 해당약물의 피크 면적비에 weighted regression(1/x)을 적용하여 작성하였다.A stock solution (1 mg/mL) was prepared by dissolving 10.00 mg of rebamipide in 10 mL of acetonitrile. After diluting the stock solution with acetonitrile, 50 μL of donor plasma and 50 μL of a previously prepared working solution were added to a micro tube, and a standard concentration of 5, 10, 50, 100, 500, and 1000 ng/mL Plasma samples were prepared. To 50 μL of the prepared standard plasma sample, 50 μL of an internal standard standard solution (Rebamipide-D4, 500 ng/mL) dissolved in acetonitrile and 350 μL of acetonitrile as a precipitation solvent were added, followed by vortexing for 3 minutes to precipitate proteins. After centrifuging this solution at 20000 g for 15 minutes, 100 μL of the supernatant was added to 100 μL of distilled water, vortexed for 3 minutes, and 5 μL was injected into LC-MS/MS. The calibration curve was prepared by applying weighted regression (1/x) to the ratio of the peak area of the drug to the peak area of the internal standard in the plasma drug concentration range.
상기와 같이 분석하여 얻어진 혈중농도 프로파일은 도 3과 같다. 도 3의 결과로부터, 본 발명에 따라 얻어진 서방성 정제는 레바미피드가 서서히 흡수되고, 지속적으로 약물 농도를 유지함을 확인할 수 있다.The blood concentration profile obtained by analyzing as described above is shown in FIG. 3. From the results of FIG. 3, it can be seen that the sustained-release tablet obtained according to the present invention gradually absorbs rebamipide and continuously maintains the drug concentration.

Claims (22)

  1. 레바미피드 또는 이의 약학적으로 허용가능한 염; 및 겔화 방지제 및 서방성 중합체로서 키토산을 포함하는, 1일 1회 혹은 1일 2회 경구투여를 위한 서방성 약학 조성물.Rebamipide or a pharmaceutically acceptable salt thereof; And a sustained-release pharmaceutical composition for oral administration once a day or twice a day, comprising chitosan as an anti-gelling agent and a sustained-release polymer.
  2. 레바미피드 또는 이의 약학적으로 허용가능한 염; 키토산 및 아미노-메타크릴레이트 공중합체로 이루어진 군으로부터 1종 이상 선택된 겔화 방지제; 및 서방성 중합체를 포함하는, 1일 1회 혹은 1일 2회 투여를 위한 서방성 약학 조성물.Rebamipide or a pharmaceutically acceptable salt thereof; At least one anti-gelling agent selected from the group consisting of chitosan and amino-methacrylate copolymers; And a sustained-release pharmaceutical composition for administration once a day or twice a day, comprising a sustained-release polymer.
  3. 제1항에 있어서, 상기 키토산이 탈아실화도가 70% 이상인 키토산인 것을 특징으로 하는 약학 조성물.The pharmaceutical composition according to claim 1, wherein the chitosan is chitosan having a degree of deacylation of 70% or more.
  4. 제2항에 있어서, 상기 키토산이 탈아실화도가 70% 이상인 키토산인 것을 특징으로 하는 약학 조성물.The pharmaceutical composition according to claim 2, wherein the chitosan is chitosan having a degree of deacylation of 70% or more.
  5. 제1항에 있어서, 상기 키토산이 레바미피드 100 중량부에 대하여 20 내지 200 중량부의 범위로 존재하는 것을 특징으로 하는 약학 조성물.The pharmaceutical composition according to claim 1, wherein the chitosan is present in a range of 20 to 200 parts by weight based on 100 parts by weight of rebamipide.
  6. 제2항에 있어서, 상기 겔화 방지제가 레바미피드 100 중량부에 대하여 20 내지 200 중량부의 범위로 존재하는 것을 특징으로 하는 약학 조성물.The pharmaceutical composition according to claim 2, wherein the anti-gelling agent is present in the range of 20 to 200 parts by weight based on 100 parts by weight of rebamipide.
  7. 제2항에 있어서, 상기 겔화 방지제가 아미노-메타크릴레이트 공중합체 및 키토산이고, 아미노-메타크릴레이트 공중합체 및 키토산의 중량비가 1∼10인 것을 특징으로 하는 약학 조성물.The pharmaceutical composition according to claim 2, wherein the anti-gelling agent is an amino-methacrylate copolymer and chitosan, and the weight ratio of the amino-methacrylate copolymer and chitosan is 1-10.
  8. 제2항에 있어서, 상기 아미노-메타크릴레이트 공중합체가 부틸 메타크릴레이트, (2-디메틸아미노에틸) 메타크릴레이트, 및 메틸 메타크릴레이트가 1 : 2 : 1의 몰비로 공중합된 공중합체인 것을 특징으로 하는 약학 조성물.The method of claim 2, wherein the amino-methacrylate copolymer is a copolymer in which butyl methacrylate, (2-dimethylaminoethyl) methacrylate, and methyl methacrylate are copolymerized in a molar ratio of 1:2:1. A pharmaceutical composition, characterized in that.
  9. 제2항에 있어서, 상기 서방성 중합체가 레바미피드 100 중량부에 대하여 10 내지 100 중량부의 범위로 존재하는 것을 특징으로 하는 약학 조성물.The pharmaceutical composition according to claim 2, wherein the sustained-release polymer is present in a range of 10 to 100 parts by weight based on 100 parts by weight of rebamipide.
  10. 제2항에 있어서, 상기 서방성 중합체가 히드록시프로필 메틸셀룰로오스, 히드록시프로필 셀룰로오스, 히드록시에틸 셀룰로오스, 에틸 셀룰로오스, 메틸 셀룰로오스, 카르복메틸 셀룰로오스, 폴리에틸렌 옥사이드, 폴리비닐 알코올, 폴리비닐피롤리돈, 잔탄 검, 구아 검, 카보머, 카라기난, 알긴산 나트륨, 폴리메타크릴레이트 공중합체, 글리세릴 비히네이트, 글리세릴 모노스테아레이트, 세틸 알콜, 및 스테아릴 알콜로 이루어진 군으로부터 1종 이상 선택되는 것을 특징으로 하는 약학 조성물.The method of claim 2, wherein the sustained-release polymer is hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl cellulose, methyl cellulose, carboxymethyl cellulose, polyethylene oxide, polyvinyl alcohol, polyvinylpyrrolidone , Xanthan gum, guar gum, carbomer, carrageenan, sodium alginate, polymethacrylate copolymer, glyceryl bihinate, glyceryl monostearate, cetyl alcohol, and stearyl alcohol. A pharmaceutical composition, characterized in that.
  11. 제10항에 있어서, 상기 서방성 중합체가 히드록시프로필 메틸셀룰로오스, 카라기난, 또는 폴리에틸렌 옥사이드인 것을 특징으로 하는 약학 조성물.The pharmaceutical composition according to claim 10, wherein the sustained-release polymer is hydroxypropyl methylcellulose, carrageenan, or polyethylene oxide.
  12. 제1항 내지 제11항 중 어느 한 항에 있어서, 희석제, 알칼리화제, 활택제, 결합제, 계면활성제, 착항제, 및 착색제로 이루어진 군으로부터 1종 이상 선택된 첨가제를 추가로 포함하는 것을 특징으로 하는 약학 조성물.The method according to any one of claims 1 to 11, further comprising at least one additive selected from the group consisting of a diluent, an alkalizing agent, a lubricant, a binder, a surfactant, a complexing agent, and a colorant. Pharmaceutical composition.
  13. 제12항에 있어서, 상기 희석제가 유당, 포도당, 미결정 셀룰로오스, 결정 셀룰로오스, 인산이수소칼슘 또는 이의 수화물, 만니톨, 이소말트, 솔비톨, 전호화 전분, 자당, 전분, 락티톨, 자일리톨, 덱스트로스, 덱스트란, 베타시클로덱스트린, 락토오즈와 셀룰로오스의 혼합물, 실리카와 미결정셀룰로오스의 혼합물, 말티톨, 및 저치환 히드록시프로필셀룰로오스로 이루어진 군으로부터 1종 이상 선택되는 것을 특징으로 하는 약학 조성물.The method of claim 12, wherein the diluent is lactose, glucose, microcrystalline cellulose, crystalline cellulose, calcium dihydrogen phosphate or a hydrate thereof, mannitol, isomalt, sorbitol, pregelatinized starch, sucrose, starch, lactitol, xylitol, dextrose, Dextran, beta cyclodextrin, a mixture of lactose and cellulose, a mixture of silica and microcrystalline cellulose, maltitol, and a pharmaceutical composition, characterized in that at least one selected from the group consisting of low-substituted hydroxypropyl cellulose.
  14. 제12항에 있어서, 상기 알칼리화제가 메글루민, 인산수소칼륨, 인산수소나트륨, 마그네슘 옥사이드, 탄산칼슘, 탄산수소칼슘, 탄산수소나트륨, 탄산나트륨, 수산화마그네슘, 수산화나트륨, 및 수산화칼륨으로 이루어진 군으로부터 1종 이상 선택되는 것을 특징으로 하는 약학 조성물.The method of claim 12, wherein the alkalizing agent is from the group consisting of meglumine, potassium hydrogen phosphate, sodium hydrogen phosphate, magnesium oxide, calcium carbonate, calcium hydrogen carbonate, sodium hydrogen carbonate, sodium carbonate, magnesium hydroxide, sodium hydroxide, and potassium hydroxide. Pharmaceutical composition, characterized in that at least one is selected.
  15. 제12항에 있어서, 상기 결합제가 폴리비닐피롤리돈, 젤라틴, 코포비돈, 히드록시메틸 셀룰로오스, 옥수수전분, 및 백당으로 이루어진 군으로부터 1종 이상 선택되는 것을 특징으로 하는 약학 조성물.The pharmaceutical composition according to claim 12, wherein the binder is selected from the group consisting of polyvinylpyrrolidone, gelatin, copovidone, hydroxymethyl cellulose, corn starch, and sucrose.
  16. 제12항에 있어서, 상기 계면활성제가 소디움 라우릴 설페이트, 폴리소르베이트, 자당 지방산 에스테르, 및 수소화 피마자유로 이루어진 군으로부터 1종 이상 선택되는 것을 특징으로 하는 약학 조성물.The pharmaceutical composition according to claim 12, wherein the surfactant is selected from the group consisting of sodium lauryl sulfate, polysorbate, sucrose fatty acid ester, and hydrogenated castor oil.
  17. 제12항에 있서, 상기 활택제가 스테아린산 또는 이의 염, 메타규산알루민산 또는 이의 염, 스테아릴푸마르산 또는 이의 염, 경질 무수규산, 팔미트산, 활석, 카르나우바 왁스, 수소화 식물성 오일, 광유, 및 폴리에틸렌 글리콜로 이루어진 군으로부터 1종 이상 선택되는 것을 특징으로 하는 약학 조성물.The method of claim 12, wherein the lubricant is stearic acid or its salt, metasilicate aluminic acid or its salt, stearyl fumaric acid or its salt, light anhydrous silicic acid, palmitic acid, talc, carnauba wax, hydrogenated vegetable oil, mineral oil, And a pharmaceutical composition, characterized in that at least one selected from the group consisting of polyethylene glycol.
  18. 제1항 내지 제11항 중 어느 한 항에 있어서, 정제, 압축과립, 또는 펠렛의 제형을 갖는 것을 특징으로 하는 약학 조성물.The pharmaceutical composition according to any one of claims 1 to 11, which has a dosage form of tablets, compressed granules, or pellets.
  19. 제18항에 있어서, 상기 제형이 건식과립법 혹은 습식과립법에 의해 제조되는 것을 특징으로 하는 약학 조성물.The pharmaceutical composition according to claim 18, wherein the formulation is prepared by a dry granulation method or a wet granulation method.
  20. 레바미피드 또는 이의 약학적으로 허용가능한 염; 및 겔화 방지제 및 서방성 중합체로서 키토산을 포함하거나; 혹은 레바미피드 또는 이의 약학적으로 허용가능한 염; 겔화 방지제로서 키토산 또는 아미노-메타크릴레이트 공중합체; 및 서방성 중합체를 포함하는 서방성 제1층; 및Rebamipide or a pharmaceutically acceptable salt thereof; And chitosan as an anti-gelling agent and a sustained-release polymer; Or rebamipide or a pharmaceutically acceptable salt thereof; Chitosan or amino-methacrylate copolymers as anti-gelling agents; And a sustained-release first layer comprising a sustained-release polymer; And
    레바미피드 또는 이의 약학적으로 허용가능한 염 및 약학적으로 허용가능한 첨가제를 포함하는 속방성 제2층Immediate-release second layer comprising rebamipide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive
    을 포함하는 레바미피드의 다중 방출 패턴을 나타내는 다층정.Multilayer tablet showing a multiple emission pattern of rebamipide comprising a.
  21. 레바미피드 또는 이의 약학적으로 허용가능한 염; 및 겔화 방지제 및 서방성 중합체로서 키토산을 포함하거나; 혹은 레바미피드 또는 이의 약학적으로 허용가능한 염; 겔화 방지제로서 키토산 또는 아미노-메타크릴레이트 공중합체; 및 서방성 중합체를 포함하는 서방성 펠렛 또는 과립; 및Rebamipide or a pharmaceutically acceptable salt thereof; And chitosan as an anti-gelling agent and a sustained-release polymer; Or rebamipide or a pharmaceutically acceptable salt thereof; Chitosan or amino-methacrylate copolymers as anti-gelling agents; And sustained-release pellets or granules containing a sustained-release polymer; And
    레바미피드 또는 이의 약학적으로 허용가능한 염 및 약학적으로 허용가능한 첨가제를 포함하는 속방성 펠렛 또는 과립Immediate-release pellets or granules containing rebamipide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive
    을 포함하는 레바미피드의 다중 방출 패턴을 나타내는 캅셀제.Capsules showing a multiple release pattern of rebamipide comprising a.
  22. 레바미피드 또는 이의 약학적으로 허용가능한 염; 및 겔화 방지제 및 서방성 중합체로서 키토산을 포함하거나; 혹은 레바미피드 또는 이의 약학적으로 허용가능한 염; 겔화 방지제로서 키토산 또는 아미노-메타크릴레이트 공중합체; 및 서방성 중합체를 포함하는 서방성 코어; 및Rebamipide or a pharmaceutically acceptable salt thereof; And chitosan as an anti-gelling agent and a sustained-release polymer; Or rebamipide or a pharmaceutically acceptable salt thereof; Chitosan or amino-methacrylate copolymers as anti-gelling agents; And a sustained-release core comprising a sustained-release polymer; And
    레바미피드 또는 이의 약학적으로 허용가능한 염 및 약학적으로 허용가능한 첨가제를 포함하는 속방성 쉘Rebamipide or a pharmaceutically acceptable salt thereof and an immediate-release shell comprising a pharmaceutically acceptable additive
    을 포함하는 레바미피드의 다중 방출 패턴을 나타내는 유핵정.A nucleated tablet showing a multiple release pattern of rebamipide comprising a.
PCT/KR2020/015184 2019-11-05 2020-11-03 Sustained-release pharmaceutical composition for oral administration, containing rebamipide or pharmaceutically acceptable salt thereof WO2021091188A1 (en)

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